EP2313422A2 - Nucleoside cyclicphosphates - Google Patents
Nucleoside cyclicphosphatesInfo
- Publication number
- EP2313422A2 EP2313422A2 EP09763386A EP09763386A EP2313422A2 EP 2313422 A2 EP2313422 A2 EP 2313422A2 EP 09763386 A EP09763386 A EP 09763386A EP 09763386 A EP09763386 A EP 09763386A EP 2313422 A2 EP2313422 A2 EP 2313422A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- optionally substituted
- methyl
- fluoro
- oxo
- furo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003833 nucleoside derivatives Chemical class 0.000 title abstract description 21
- 239000002777 nucleoside Substances 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 150000004677 hydrates Chemical class 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 359
- 229910052801 chlorine Inorganic materials 0.000 claims description 348
- 229910052794 bromium Inorganic materials 0.000 claims description 336
- 229910052740 iodine Inorganic materials 0.000 claims description 287
- 125000004432 carbon atom Chemical group C* 0.000 claims description 269
- 125000000217 alkyl group Chemical group 0.000 claims description 264
- -1 OCH2CH3 Chemical group 0.000 claims description 196
- 125000000623 heterocyclic group Chemical group 0.000 claims description 164
- 229910052739 hydrogen Inorganic materials 0.000 claims description 151
- 125000003545 alkoxy group Chemical group 0.000 claims description 147
- 125000000304 alkynyl group Chemical group 0.000 claims description 119
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 110
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 103
- 125000001624 naphthyl group Chemical group 0.000 claims description 99
- 125000003342 alkenyl group Chemical group 0.000 claims description 81
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 78
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 67
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 64
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 63
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 58
- 125000002252 acyl group Chemical group 0.000 claims description 57
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 56
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 54
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 54
- 229920002554 vinyl polymer Polymers 0.000 claims description 54
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 52
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 52
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 52
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 44
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 40
- 241000711549 Hepacivirus C Species 0.000 claims description 40
- AQIAIZBHFAKICS-UHFFFAOYSA-N methylaminomethyl Chemical compound [CH2]NC AQIAIZBHFAKICS-UHFFFAOYSA-N 0.000 claims description 40
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 29
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 28
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 28
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 208000015181 infectious disease Diseases 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 238000011321 prophylaxis Methods 0.000 claims description 10
- 230000003612 virological effect Effects 0.000 claims description 10
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 241000710842 Japanese encephalitis virus Species 0.000 claims description 5
- 241000710772 Yellow fever virus Species 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 229940051021 yellow-fever virus Drugs 0.000 claims description 5
- 241000709661 Enterovirus Species 0.000 claims description 4
- 241000991587 Enterovirus C Species 0.000 claims description 4
- 241000709721 Hepatovirus A Species 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
- 241000710886 West Nile virus Species 0.000 claims description 4
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003212 purines Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 241000725619 Dengue virus Species 0.000 claims 2
- CWRWBPZRJIEILF-PJOQMFMOSA-N 9-[(2r,4ar,6r,7r,7ar)-2-butoxy-7-fluoro-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-2-amino-3h-purin-6-one Chemical compound C1=NC2=C(O)N=C(N)N=C2N1[C@@H]1O[C@@H]2CO[P@](OCCCC)(=O)O[C@H]2[C@]1(F)C CWRWBPZRJIEILF-PJOQMFMOSA-N 0.000 claims 1
- YUJFUPWFGNVDET-FNETUSETSA-N 9-[(2r,4ar,6r,7r,7ar)-7-fluoro-7-methyl-2-oxo-2-propoxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-2-amino-3h-purin-6-one Chemical compound C1=NC2=C(O)N=C(N)N=C2N1[C@@H]1O[C@@H]2CO[P@](OCCC)(=O)O[C@H]2[C@]1(F)C YUJFUPWFGNVDET-FNETUSETSA-N 0.000 claims 1
- IXDHARARUWRPQS-CJRBIKLJSA-N 9-[(2s,4ar,6r,7r,7ar)-2-butoxy-7-fluoro-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-propoxypurin-2-amine Chemical compound C1=NC2=C(OCCC)N=C(N)N=C2N1[C@@H]1O[C@@H]2CO[P@@](OCCCC)(=O)O[C@H]2[C@]1(F)C IXDHARARUWRPQS-CJRBIKLJSA-N 0.000 claims 1
- JNTCRUIACSNWCD-DSQUMVBZSA-N 9-[(2s,4ar,6r,7r,7ar)-7-fluoro-7-methyl-2-oxo-2-propoxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-ethoxypurin-2-amine Chemical compound C1=NC2=C(OCC)N=C(N)N=C2N1[C@@H]1O[C@@H]2CO[P@@](OCCC)(=O)O[C@H]2[C@]1(F)C JNTCRUIACSNWCD-DSQUMVBZSA-N 0.000 claims 1
- JUKMZWOCKDQWQA-IRFXWXKVSA-N 9-[(2s,4ar,6r,7r,7ar)-7-fluoro-7-methyl-2-oxo-2-propoxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-phenylmethoxypurin-2-amine Chemical compound N1=C(N)N=C2N([C@@H]3O[C@@H]4CO[P@](O[C@H]4[C@]3(F)C)(=O)OCCC)C=NC2=C1OCC1=CC=CC=C1 JUKMZWOCKDQWQA-IRFXWXKVSA-N 0.000 claims 1
- YHNAVECCZUVMQD-WCTLDAENSA-N 9-[(4ar,6r,7r,7ar)-2-butoxy-7-fluoro-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-n-propylpurine-2,6-diamine Chemical compound C1=NC2=C(NCCC)N=C(N)N=C2N1[C@@H]1O[C@@H]2COP(OCCCC)(=O)O[C@H]2[C@]1(F)C YHNAVECCZUVMQD-WCTLDAENSA-N 0.000 claims 1
- SYUSODIXCBJNRD-GSWPYSDESA-N 9-[(4ar,6r,7r,7ar)-7-fluoro-2-hydroxy-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-methoxypurin-2-amine Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@](F)(C)[C@@H]2N1C(N=C(N)N=C2OC)=C2N=C1 SYUSODIXCBJNRD-GSWPYSDESA-N 0.000 claims 1
- LHHSWZPKURNUCA-BHAIJONBSA-N 9-[(4ar,6r,7r,7ar)-7-fluoro-2-methoxy-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-phenylmethoxypurin-2-amine Chemical compound N1=C(N)N=C2N([C@@H]3O[C@@H]4COP(O[C@H]4[C@]3(F)C)(=O)OC)C=NC2=C1OCC1=CC=CC=C1 LHHSWZPKURNUCA-BHAIJONBSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 7
- 239000010452 phosphate Substances 0.000 abstract description 7
- 125000004122 cyclic group Chemical group 0.000 abstract description 5
- 241000124008 Mammalia Species 0.000 abstract description 4
- 208000036142 Viral infection Diseases 0.000 abstract description 2
- 230000009385 viral infection Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 55
- 239000000047 product Substances 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 42
- 239000007787 solid Substances 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 125000004104 aryloxy group Chemical group 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 17
- 229910052760 oxygen Inorganic materials 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 241000710778 Pestivirus Species 0.000 description 15
- 241000700605 Viruses Species 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- 241000711557 Hepacivirus Species 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 125000005843 halogen group Chemical group 0.000 description 13
- 238000004679 31P NMR spectroscopy Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 11
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 9
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 235000021317 phosphate Nutrition 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- NKAUAYQORRVTFN-NMRNUDPRSA-N [(2r,3r,4r,5r)-5-(2-amino-6-chloropurin-9-yl)-3-benzoyloxy-4-fluoro-4-methyloxolan-2-yl]methyl benzoate Chemical compound O([C@H]1[C@]([C@@H](O[C@@H]1COC(=O)C=1C=CC=CC=1)N1C2=NC(N)=NC(Cl)=C2N=C1)(F)C)C(=O)C1=CC=CC=C1 NKAUAYQORRVTFN-NMRNUDPRSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 101710144111 Non-structural protein 3 Proteins 0.000 description 6
- 239000003443 antiviral agent Substances 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- 150000003536 tetrazoles Chemical class 0.000 description 6
- 108060004795 Methyltransferase Proteins 0.000 description 5
- 108010076039 Polyproteins Proteins 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- JKQHPHSOLRHCPT-AMJCQUEASA-N (2r,3r,4r,5r)-5-[2-amino-6-(azetidin-1-yl)purin-9-yl]-4-fluoro-2-(hydroxymethyl)-4-methyloxolan-3-ol Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC(N)=NC(N3CCC3)=C2N=C1 JKQHPHSOLRHCPT-AMJCQUEASA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000710781 Flaviviridae Species 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 102000006992 Interferon-alpha Human genes 0.000 description 4
- 108010047761 Interferon-alpha Proteins 0.000 description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 description 4
- 229910006069 SO3H Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 125000000033 alkoxyamino group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 4
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 125000003835 nucleoside group Chemical group 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 239000001226 triphosphate Substances 0.000 description 4
- 235000011178 triphosphate Nutrition 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 101800001020 Non-structural protein 4A Proteins 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- 102000012479 Serine Proteases Human genes 0.000 description 3
- 108010022999 Serine Proteases Proteins 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 108010067390 Viral Proteins Proteins 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- OWGOJLZTHHOZEF-UHFFFAOYSA-N bis[di(propan-2-yl)amino]methoxyphosphonamidous acid Chemical compound CC(C)N(C(C)C)C(OP(N)O)N(C(C)C)C(C)C OWGOJLZTHHOZEF-UHFFFAOYSA-N 0.000 description 3
- PXMINALWPRIRHV-UHFFFAOYSA-N bis[di(propan-2-yl)amino]methyl dihydrogen phosphite Chemical compound CC(C)N(C(C)C)C(OP(O)O)N(C(C)C)C(C)C PXMINALWPRIRHV-UHFFFAOYSA-N 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229940095102 methyl benzoate Drugs 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000008520 organization Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IBPVHPXXSOANJN-VHQAPHLWSA-N (2r,3r,4r,5r)-5-(2-amino-6-ethoxypurin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyloxolan-3-ol Chemical compound C1=NC=2C(OCC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F IBPVHPXXSOANJN-VHQAPHLWSA-N 0.000 description 2
- CEZAHINTASCQLC-GSWPYSDESA-N (2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyloxolan-3-ol Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F CEZAHINTASCQLC-GSWPYSDESA-N 0.000 description 2
- LVUJNPOMTHBGJH-MAAOGQSESA-N (2r,3r,4r,5r)-5-(2-amino-6-phenylmethoxypurin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyloxolan-3-ol Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC(N)=NC(OCC=3C=CC=CC=3)=C2N=C1 LVUJNPOMTHBGJH-MAAOGQSESA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- AVLPJGHIUGVLIX-GBIGWYSMSA-N 9-[(4ar,6r,7r,7ar)-7-fluoro-2-methoxy-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-(azetidin-1-yl)purin-2-amine Chemical compound N1=C(N)N=C2N([C@@H]3O[C@@H]4COP(O[C@H]4[C@]3(F)C)(=O)OC)C=NC2=C1N1CCC1 AVLPJGHIUGVLIX-GBIGWYSMSA-N 0.000 description 2
- RQOXEYZWZIVIQI-UYISCHNFSA-N 9-[(4ar,6r,7r,7ar)-7-fluoro-2-methoxy-7-methyl-2-oxo-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-n-cyclobutylpurine-2,6-diamine Chemical compound N1=C(N)N=C2N([C@@H]3O[C@@H]4COP(O[C@H]4[C@]3(F)C)(=O)OC)C=NC2=C1NC1CCC1 RQOXEYZWZIVIQI-UYISCHNFSA-N 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 241001118702 Border disease virus Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000710777 Classical swine fever virus Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 101710118188 DNA-binding protein HU-alpha Proteins 0.000 description 2
- 206010012310 Dengue fever Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241000710831 Flavivirus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000531123 GB virus C Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101710144128 Non-structural protein 2 Proteins 0.000 description 2
- 101800001019 Non-structural protein 4B Proteins 0.000 description 2
- 101800001014 Non-structural protein 5A Proteins 0.000 description 2
- 101710199667 Nuclear export protein Proteins 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 229940123066 Polymerase inhibitor Drugs 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 108030002536 RNA-directed RNA polymerases Proteins 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- BXKUNDXPWMNAMP-YAJHFMINSA-N [(2r,3r,4r,5r)-3-benzoyloxy-5-bromo-4-fluoro-4-methyloxolan-2-yl]methyl benzoate Chemical compound C([C@H]1O[C@H](Br)[C@@]([C@@H]1OC(=O)C=1C=CC=CC=1)(F)C)OC(=O)C1=CC=CC=C1 BXKUNDXPWMNAMP-YAJHFMINSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 201000002950 dengue hemorrhagic fever Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 230000000405 serological effect Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- MEXSXDCMCCIVFV-GITKWUPZSA-N 2-amino-9-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]-3h-purin-6-one Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(N)=NC2=O)=C2N=C1 MEXSXDCMCCIVFV-GITKWUPZSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- SFYDWLYPIXHPML-UHFFFAOYSA-N 3-nitro-1-(2,4,6-trimethylphenyl)sulfonyl-1,2,4-triazole Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)N1N=C([N+]([O-])=O)N=C1 SFYDWLYPIXHPML-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- SVXNJCYYMRMXNM-UHFFFAOYSA-N 5-amino-2h-1,2,4-triazin-3-one Chemical compound NC=1C=NNC(=O)N=1 SVXNJCYYMRMXNM-UHFFFAOYSA-N 0.000 description 1
- NPYPQKXJJZZSAX-UHFFFAOYSA-N 5-benzylpyrimidine Chemical class C=1N=CN=CC=1CC1=CC=CC=C1 NPYPQKXJJZZSAX-UHFFFAOYSA-N 0.000 description 1
- LZGICTBSBIWVFA-UHFFFAOYSA-N 5-bromo-2-ethenylpyrimidine Chemical compound BrC1=CN=C(C=C)N=C1 LZGICTBSBIWVFA-UHFFFAOYSA-N 0.000 description 1
- HXXVIKZQIFTJOQ-UHFFFAOYSA-N 5-ethenylpyrimidine Chemical compound C=CC1=CN=CN=C1 HXXVIKZQIFTJOQ-UHFFFAOYSA-N 0.000 description 1
- DNWRLMRKDSGSPL-UHFFFAOYSA-N 5-iodopyrimidine Chemical compound IC1=CN=CN=C1 DNWRLMRKDSGSPL-UHFFFAOYSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- NOYDQGFVFOQSAJ-UHFFFAOYSA-N 5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=CN=C1 NOYDQGFVFOQSAJ-UHFFFAOYSA-N 0.000 description 1
- 108091027075 5S-rRNA precursor Proteins 0.000 description 1
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 1
- PVRBGBGMDLPYKG-UHFFFAOYSA-N 6-benzyl-7h-purine Chemical compound N=1C=NC=2N=CNC=2C=1CC1=CC=CC=C1 PVRBGBGMDLPYKG-UHFFFAOYSA-N 0.000 description 1
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 1
- DBCMWACNZJYUHS-UHFFFAOYSA-N 6-ethenyl-7h-purine Chemical compound C=CC1=NC=NC2=C1NC=N2 DBCMWACNZJYUHS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OMSPNIGCBQFQFQ-UHFFFAOYSA-N BrC1=CC=NC(C=C)=N1 Chemical compound BrC1=CC=NC(C=C)=N1 OMSPNIGCBQFQFQ-UHFFFAOYSA-N 0.000 description 1
- MWKOXNSZLORNCE-UHFFFAOYSA-N CC(C)N(C(C)C)C(C1=CC=CC=C1)(N(C(C)C)C(C)C)P(O)(O)O Chemical compound CC(C)N(C(C)C)C(C1=CC=CC=C1)(N(C(C)C)C(C)C)P(O)(O)O MWKOXNSZLORNCE-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 231100000036 EC90 Toxicity 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241000414862 GBV-A-like agents Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229940124683 HCV polymerase inhibitor Drugs 0.000 description 1
- 229940122604 HCV protease inhibitor Drugs 0.000 description 1
- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 229940121759 Helicase inhibitor Drugs 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010011356 Nucleoside phosphotransferase Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 241000682990 Pegivirus A Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 208000004571 Pestivirus Infections Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 1
- 208000009714 Severe Dengue Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000272534 Struthio camelus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 238000002832 anti-viral assay Methods 0.000 description 1
- 229940124977 antiviral medication Drugs 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- HGQULGDOROIPJN-UHFFFAOYSA-N azetidin-1-ium;chloride Chemical compound Cl.C1CNC1 HGQULGDOROIPJN-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 108091092328 cellular RNA Proteins 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- LXWYCLOUQZZDBD-LIYNQYRNSA-N csfv Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LXWYCLOUQZZDBD-LIYNQYRNSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000005436 dihydrobenzothiophenyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004597 dihydrobenzothiopyranyl group Chemical group S1C(CCC2=C1C=CC=C2)* 0.000 description 1
- 125000005435 dihydrobenzoxazolyl group Chemical group O1C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005051 dihydropyrazinyl group Chemical group N1(CC=NC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005053 dihydropyrimidinyl group Chemical group N1(CN=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005058 dihydrotriazolyl group Chemical group N1(NNC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940072240 direct acting antivirals Drugs 0.000 description 1
- 229940125371 direct-acting antiviral drugs Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940125777 fusion inhibitor Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical compound [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000025858 pestivirus infectious disease Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052573 porcelain Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 1
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 239000003970 toll like receptor agonist Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- the present invention pertains to nucleoside cyclic phosphates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA- dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.
- the invention provides novel chemical compounds, and the use of these compounds alone or in combination with other antiviral agents for treating HCV infection.
- Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
- chronic liver disease such as cirrhosis and hepatocellular carcinoma
- According to the World Health Organization there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives.
- Ten to twenty percent of chronically infected individuals eventually develop liver- destroying cirrhosis or cancer.
- the viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring.
- Current treatments for HCV infection which are restricted to immunotherapy with recombinant interferon- ⁇ alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit as resistance develops rapidly.
- the HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids.
- the protein products of the HCV gene consist of the structural proteins C, El, and E2, and the non-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B.
- the nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication.
- the NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain.
- HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. Therefore, NS5B polymerase is considered to be an essential component in the HCV replication complex (K. Ishi, et al, Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118). Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.
- HCV belongs to a much larger family of viruses that share many common features.
- the Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flavivruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole member is HCV.
- the flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993,70,37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever ⁇ Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P.
- Flaviviruses of global concern that are associated with human disease include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., New Eng. J. Med, 1988, 319, 64 1-643).
- DHF Dengue Hemorrhagic Fever viruses
- Yellow fever virus yellow fever virus
- shock syndrome and Japanese encephalitis virus
- the pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, HJ., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans.
- BVDV bovine viral diarrhea virus
- CSFV classical swine fever virus
- BDV border disease virus
- Pestiviruses and hepaciviruses are closely related virus groups within the Flaviviridae family.
- Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV).
- the hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are at least 6 HCV genotypes and more than 50 subtypes.
- bovine viral diarrhea virus Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.
- BVDV bovine viral diarrhea virus
- RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins.
- the viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed nonstructural (NS) proteins.
- NS nonstructural
- the mature nonstructural (NS) proteins in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
- the NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions.
- the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine proteinases and of helicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and Fletterick Virology , 1989,171,637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17, 3889-3897).
- the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. and Dolja, V.V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).
- NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett, Virology, 1991, 184, 341-350; Bartenschlager et al., J Virol. 1993, 67, 3835-3844; Eckart et al. Biochem. Biophys. Res. Comm. 1993,192, 399-406; Grakoui et al., J Virol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl.
- NS4A protein acts as a cofactor with the NS3 serine protease (Bartenschlager et al., J. Virol. 1994, 68, 5045-5055; Failla et al., J. Virol. 1994, 68, 3753-3760; Xu et al., J. Virol, 1997, 71:53 12-5322).
- the NS3 protein of both viruses also functions as a helicase (Kim et al., Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J Virol. 1995, 69,1720-1726).
- the NS5B proteins of pesti viruses and hepaciviruses have the predicted RNA-directed RNA polymerases activity (Behrens et al, EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol, 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J Virol, 1998, 72, 9365-9369).
- RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome and this enzyme has elicited significant interest among medicinal chemists.
- Inhibitors of HCV NS5B as potential therapies for HCV infection have been reviewed: Tan, S.-L., etal., Nature Rev. DrugDiscov., 2002, 1, 867-881; Walker, M.P. etal., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., etal., Current Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu, P.
- Nucleoside inhibitors of NS5B polymerase can act either as a non-natural substrate that results in chain termination or as a competitive inhibitor which competes with nucleotide binding to the polymerase.
- the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation.
- nucleoside cyclic phosphate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (PCT Int. App. WO 2007/027248 A2; Bi-Organic and Medicinal Chemistry Letters, 2007, VoI 17, Page 2452-2455; Journal of American Chemical Society, 1990, VoI 112, Page 7475-7482.)
- nucleosides are limiting the utility of nucleosides as viable therapeutic agents. Also limiting the utility of nucleosides as viable therapeutic agents is their sometimes poor physicochemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of nucleosides have been employed.
- the present invention is directed toward novel cyclic phosphate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, deuterated analogues, or crystalline forms thereof, represented by the following structure:
- R 1 is hydrogen, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR 1 , NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl of C 2 - C 6 , such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I
- R 2 is H, an optionally substituted alkyl (including lower alkyl), cyano (CN), CH 3 , vinyl, O-alkyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl alkyl, i.e., -(CH 2 ) 0 0H, wherein o is 1 - 10, hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , F, or CN;
- X is H, OH, F, OMe, halogen, NH 2 , or N 3
- Base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
- Z is N or CR 9 ;
- R 4 , R 5 ,R 6 , R 7 , and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 , NHR', NR' 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the Base may be selected from a group of formula c'
- Z is independently selected from N or C-G; or, if Z is not a participant in a pi bond (double bond), Z is independently selected from O, S, Se, NR 11 , NOR 11 , NNR U 2 , CO, CS, CNR 11 , SO, S(O) 2 , SeO, Se(O) 2 , or C(G) 2 ; each G is independently selected from the group consisting of H, halogen,
- OR 11 , SR 11 , NR ⁇ 2 , NR 11 OR 11 , N 3 , COOR 11 , CN, CONR ⁇ 2 , C(S)NR n 2 , C( NR 11 )NR 11 2 , and R 11 ; and where any two adjacent Z are not both selected from O, S, and Se, or not both selected from CO, CS, CNNR 11 , SO, S(O) 2 , SeO and Se(O)
- each R is independently selected from the group consisting of H, CF 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heteroaryl, optional
- Base may be a structure selected from the group consisting of structures o - ff
- Base may be a structure gg
- each Z' is independently N (if a participant in a pi bond) or NR (if ot a participant in a pi bond) and R 10 , R 11 , and Z are defined as in structure c';
- Base may be a structure hh
- each Z' is independently N (if a participant in a pi bond) or NR 11 (if ot a participant in a pi bond), and each Z in independently CG (if a participant in a pi bond) or >C(G) 2 (if not a participant in a pi bond), wherein R 10 and G are defined as in structure c';
- Base may be a structure ii
- Base may be a structure jj
- Base may be a structure kk
- R is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
- Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
- V is selected from the group consisting of N and C-G;
- Z is selected from the group consisting of N and C-G;
- G and G 1 are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, - SO 3 H,
- Base may be a structure 11
- R 15 is hydrogen or C 1 -C 3 alkyl
- Q' is selected from the group consisting of NH, O, and S;
- G' is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, -SO 3 H, -SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR 13 NCHR 14 C(O)NH-, azido, cyano, halo, hydroxyamino, and hydrazino, where R 13 is hydrogen and R 14 is a side-chain of an amino acid or where R 13 and R 14 together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; or
- Base may be a structure mm mm
- R 16 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
- T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -aUcoxy, CrQ-thioalkoxy, amino, substituted amino, and halo;
- Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W 5 W 1 .
- the Base can be selected from among structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted below.
- a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
- a compound refers to one or more compounds or at least one compound.
- the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
- the one or more substituents can include alkyl, halogenated alkyl, cycloalkyl, alkenyl, ... aryl, and the like.
- an alkyl can be substituted by an alkyl (i.e., methyl, ethyl, propyl, etc.), a cycloalkyl (c-propyl, c-butyl, c- pentyl, c-hexyl, etc.), or an aryl (phenyl, substituted phenyl, naphthyl, substituted naphtyl, etc.).
- both R's can be carbon, both R's can be nitrogen, or one R' can be carbon and the other nitrogen.
- alkyl refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms.
- C 1-M alkyl refers to an alkyl comprising 2 to N carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
- C 1-4 alkyl refers to an alkyl containing 1 to 4 carbon atoms.
- lower alkyl denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms.
- C 1-20 alkyl refers to an alkyl comprising 1 to 20 carbon atoms.
- C ⁇ 10 alkyl refers to an alkyl comprising 1 to 10 carbons.
- alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i- propyl, w-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
- the term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a heteroaryl group respectively.
- halogenated alkyl refers to an unbranched or branched chain alkyl comprising at least one of F, Cl, Br, and I.
- Cr 3 haloalkyl refers to a haloalkyl comprising 1 to 3 carbons and at least one of F, Cl, Br, and I.
- halogenated lower alkyl refers to a haloalkyl comprising 1 to 6 carbon atoms and at least one of F, Cl, Br, and I.
- Examples include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1- iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2- difluoroethyl, 2,2-dichloroethyl, 2,2-dibromomethyl, 2-2-diiodomethyl, 3- fluoropropyl, 3-chloropropyl, 3-bromopropyl, 2,2,2-trifluoroethyl or 1,1,2,2,2- pentafluoroethyl.
- cycloalkyl refers to a saturated carbocyclic ring comprising 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
- C 3-7 cycloalkyl refers to a cycloalkyl comprising 3 to 7 carbons in the carbocyclic ring.
- alkenyl refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefmic double bonds, preferably one olefmic double bond.
- C 2-N alkenyl refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
- C 2 - 10 alkenyl refers to an alkenyl comprising 2 to 10 carbon atoms.
- C 2-4 alkenyl refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2- propenyl (allyl) or 2-butenyl (crotyl).
- halogenated alkenyl refers to an alkenyl comprising at least one OfF 5 Cl, Br, and I.
- alkynyl refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond.
- C 2-N alkynyl refers to an alkynyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
- C C 2-4 alkynyl refers to an alkynyl comprising 2 to 4 carbon atoms.
- C 2 - 10 alkynyl refers to an alkynyl comprising 2 to 10 carbons. Examples include, but are limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl or 3-butynyl.
- halogenated alkynyl refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond and at least one of F, Cl, Br, and I.
- alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, i- propyloxy, w-butyloxy, z-butyloxy, t-butyloxy.
- Lower alkoxy denotes an alkoxy group with a “lower alkyl” group as previously defined.
- Cyr 10 alkoxy refers to an-O-alkyl wherein alkyl is C 1-10 .
- alkoxyalkyl refers to an alkyl-O-alkyl group, wherein alkyl is defined above. Examples include, but are not limited to, methoxymethyl, ethoxymethyl, n-propyloxymethyl, z-propyloxymethyl, n-butyloxymethyl, i- butyloxymethyl, t-butyloxymethyl, and the like, methoxyethyl, ethoxyethyl, n- propyloxyethyl, z-propyloxyethyl, »-butyloxyethyl, z-butyloxyethyl, t-butyloxyethyl, and the like, methoxypropyl, ethoxypropyl, n-propyloxypropyl, z-propyloxypropyl, «-butyloxypropyl, z-butyloxypropyl, t-butyloxypropyl, and the like, meth
- halogenated alkoxy refers to an -O-alkyl group in which the alkyl group comprises at least one of F, Cl, Br, and I.
- halogenated lower alkoxy refers to an -O-(lower alkyl) group in which the lower alkyl group comprises at least one of F, Cl, Br, and I.
- alkylamino or arylamino refer to an amino group that has one or two alkyl or aryl substituents, respectively.
- protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
- oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
- Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1, 1,3,3- tetraisopropyldisiloxanylidene) .
- aryl refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl.
- the aryl group can be substituted with one or more moieties selected from among hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.
- alkaryl or “alkylaryl” refer to an alkyl group with an aryl substituent. It is understood that the aryl substituent of the "alkaryl” or “alkylaryl” can be substituted with at least one of a halogen (F, Cl, Br, or I), -hydroxyl, a lower alkoxy, such as -OCH 3 , -amino, or an alkylamino, such as -NHR or -NR 2 , where R is a lower alkyl, such as -NHCH 3 or -N(CH 3 ) 2 .
- a halogen F, Cl, Br, or I
- lower alkylaryl denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms that is substituted with a substituted or unsubstituted aryl, such as, benzyl.
- aryl or arylalkyl refer to an aryl group with an alkyl substituent.
- halo includes chloro, bromo, iodo and fluoro.
- acyl refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety.
- the carbonyl moiety contains a double-bond between the carbonyl carbon and a heteroatom, where the heteroatom is selected from among O, N and S.
- the heteroatom is selected from among O, N and S.
- the heteroatom is N, the N is substituted by a lower alkyl.
- the non- carbonyl moiety is selected from straight, branched, or cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic C 1-20 alkyl, C 1-10 alkyl, or lower alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyl optionally substituted with halogen (F, Cl, Br, I), hydroxyl, C 1 to C 4 alkyl, or C 1 to C 4 alkoxy, sulfonate esters, such as alkyl or aralkyl sulphonyl, including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or dipheny
- lower acyl refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
- purine or "pyrimidine” base includes, but is not limited to, adenine, N ⁇ alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 - acetylenic purine, N 6 -acyl purine, N ⁇ -hydroxyalkyl purine, N 6 -allylaminopurine, N 6 - thioallyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5- fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C 5 -
- Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6- diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t- butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- heterocycle or “heterocyclyl” as used herein refers to any 3-, 4-, 5-, 6-, 8-, 9-, 10-, or 11-membered saturated or unsaturated ring containing carbon atoms and from one to three heteroatoms independently selected from the group consisting of one, two, or three nitrogens, one oxygen and one nitrogen, and one sulfur and one nitrogen and including any bicyclic group in which any of the defined heterocyclic ring(s) is fused to a benzene ring; wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, wherein the nitrogen heteroatoms may be optionally quaternized, and wherein one or more carbon or nitrogen atoms may be substituted with a lower alkyl.
- heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, and the like.
- heterocycle or “heterocyclyl” include, but are not limited to the following: azepanyl, benzimidazolyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzothiofuranyl, benzothiophenyl, benzothiopyranyl, benzoxazepinyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, diazepanyl, diazapinonyl, dihydrobenzofuranyl, dihydrobenzofuryl, dihydrobenzoimidazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, diydrobenzothiopyranyl sulfone, dihydrobenzothiophenyl
- deuterated analogues refer to compounds in which at least one hydrogen atom of the compound of formula I is replaced with at least one deuterium atom.
- P* means that the phosphorous atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R” or "S” which have their accepted plain meanings.
- An aspect of the invention is directed to a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, deuterated analogues, or crystalline forms thereof, and the like represented by formula I:
- R 1 is hydrogen, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR 1 , NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl of C 2 - C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br,
- R 2 is H, an optionally substituted alkyl (including lower alkyl), cyano (CN), CH 3 , vinyl, O-alkyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl alkyl, i.e., -(CH 2 ) 0 0H, wherein o is 1 - 10, hydroxyl lower alkyl, i.e., -(CH 2 ) p 0H, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , F, or CN;
- X is H, OH, F, OMe, halogen, NH 2 , or N 3 ;
- the base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
- Z is N or CR 9 ;
- R 4 , R 5 ,R 6 , R 7 , and R 8 are independently H, F, Cl, Br, I, OH, OR, such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR, NH 2 , NHR', NR f 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the Base may be selected from a group of formula c 1
- Base may be a structure selected from the group consisting of structures d'-n
- Base may be a structure selected from the group consisting of structures o - ff
- Base may be a structure gg
- each Z' is independently N (if a participant in a pi bond) or NR (if irrttiicciippaanntt iinn aa ppii bboonndd)) aanndd I R 10 , R 11 , and Z are defined as in structure c';
- Base may be a structure hh
- each Z' is independently N (if a participant in a pi bond) or NR 11 (ifrticipant in a pi bond), and each Z in independently CG (if a participant in a) or >C(G) 2 (if not a participant in a pi bond), wherein R 10 and G are defineducture c';
- Base may be a structure ii
- Base may be a structure jj
- R 11 and G are defined as in structure c'; or Base may be a structure kk
- R 12 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
- Q is absent or is selected from the group consisting of O, S, and NH, provided that when Q is absent, V and NH are both attached to a CH 2 group;
- V is selected from the group consisting of N and C-G;
- Z is selected from the group consisting of N and C-G 1 ;
- G and G' are independently selected from the group consisting of hydrogen, amino, aminocarbonyl, methylamino, dimethylamino, acylamino, alkoxyamino, - SO 3 H, -SO 2 NH 2 , aminocarbonylamino, oxycarbonylamino, HR 13 NCHR 14 C(O)NH-, azido, cyano, halo, hydroxyamino, and hydrazino, where R 13 is hydrogen and R 14 is a side- chain of an amino acid or where R 13 and R 14 together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; with the proviso that V and Z are not identical and
- T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 -alkoxy, CrQ-thioalkoxy, amino, substituted amino, and halo; and each of W, W 1 , and W 2 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and a prodrug group; or
- Base may be a structure 11
- R 15 is hydrogen or C 1 -C 3 alkyl
- Q' is selected from the group consisting of NH, O, and S;
- G' is selected from the group consisting of amino, aminocarbonyl, methylamino, dimethylamino, acylamino, -SO 3 H, -SO 2 NH 2 , alkoxyamino, aminocarbonylamino, oxycarbonylamino, HR 13 NCHR 14 C(O)NH-, azido, cyano, halo, hydroxyamino, and hydrazino, where R 13 is hydrogen and R 14 is a side-chain of an amino acid or where R 13 and R 14 together with the nitrogen and carbon bound to each group respectively form a pyrrolidinyl group; or
- Base may be a structure mm mm
- R 16 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
- T 1 and T 2 are independently selected from the group consisting of hydrogen, hydroxyl, d-C 4 -alkoxy, d-Grthioalkoxy, amino, substituted amino, and halo;
- Y is selected from the group consisting of a bond, O, and CH 2 ; and each of W, W 1 .
- the Base can be selected from among structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted below.
- a first embodiment of the invention is directed to a compound represented by formula 1-1:
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower
- R is H, lower alkyl, cyano (CN), CH 3 , vinyl, lower alkoxy, including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , ethynyl alkyne (optionally substituted), or halogen, including F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , F, or CN;
- X is H, OH, F, OMe, halogen, NH 2 , or N 3 ;
- R 4 , R 5 , R 6 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl Of C 2 -C 6 , CO 2 H, CO 2 R', CONH 2 , CONHR 1 , C0NR' 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a first aspect of the first embodiment is directed to a compound represented by formula 1-1 wherein
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including
- OCH 3 OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 , R 5 , R 6 are independently H, F, Cl, Br, I, OH, OR, such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 , NHR, NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl Of C 2 -C 6 , CO 2 H, CO 2 R, CONH 2 , CONHR, C0NR' 2 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- a second aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alk
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and
- R 6 is selected from among OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 ,
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- a third aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR, SH, SR, NH 2 , NHR 1 , NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl Of C 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl Of C 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and
- R 6 is selected from among OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHR 2 + , NR' 3 + , OC(O)(C 1-20 alkyl), which include but are not limited to OC(O)(CH 2 ) S CH 3 , NHC(O)(C 1-20 alkyl), which include but are not limited to NHC(O)(CH 2 ) S CH 3 , N(C(O)(CH 2 ) S CH 3 ) 2 , which include but is not limited to N(C(O)(CH 2 ) S CH 3 ) 2 , where s is an integer selected from O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- a fourth aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is F
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and
- R 6 is selected from among OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NR' 2 , OC(O)(Cl-20 alkyl), which include but are not limited to OC(O)(CH 2 ) S CH 3 ,
- NHC(O)(CMO alkyl which include but are not limited to NHC(O)(CH 2 ) S CH 3 , N(C(O)(CH 2 ) S CH 3 ) 2 , which include but is not limited to N(C(O)(CH 2 ) S CH 3 ) 2 , where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- a fifth aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as G ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C
- R 3 is CH 3 ;
- R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and
- R 6 is selected from among -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , NR 2 , NHR' 2 + , NR 3 + , -OC(O)CH 3 , -NHC(O)CH 3 , -N(C(O)CH 3 ) 2 ;
- R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a sixth aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , lower alkyl, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C 6 ;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- X is F;
- R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and
- R 6 is selected from among -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , NR' 2 , NHR' 2 + , NR' 3 + , -OC(O)CH 3 , -NHC(O)CH 3 , -N(C(O)CH 3 ) 2 ,
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a seventh aspect of the first embodiment is directed to a compound represented by formula 1-1
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl 5 Br, I, OH, OR', SH, SR, NH 2 , NHR', NR 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H
- R 3 is CH 3 ;
- R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ; and (f) R 6 is selected from among -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , NR' 2 , NHR' 2 + , NR' 3 + , -OC(O)CH 3 , -NHC(O)CH 3 , -N(C(O)CH 3 ) 2 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a second embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula b above, wherein R 1 , R 2 , R 3 , X, Y, R 4 , and R 5 are defined in the Summary of the Invention section above.
- a first aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR 2 , MIR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 and R 5 are independently H, F, Cl, Br, I, OH, OR, SH, SR, NH 2 , NHR', NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of C 2 -C 6 , CO 2 H, CO 2 R, CONH 2 , CONHR', CONR 2 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the second aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the third aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR 1 , NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the fourth aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl Of C 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alk
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- R 4 and R 5 are independently H, F, Cl, OH, OCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the fifth aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl Of C 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alk
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the sixth aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br
- R 3 is CH 3 ;
- R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R 1 comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the seventh aspect of the second embodiment is directed to a compound represented by formula 1-2
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H
- R 3 is CH 3 ;
- X is F; and (e) R 4 and R 5 are independently H, F, CH 3 , CH 3-q F q , and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a third embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula c above.
- the first aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C
- R is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 ,
- NHR 1 , NIf 2 , NR' 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 -C 6 , lower alkynyl of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R, CONH 2 , CONHR', C0NR' 2 , CH CHCO 2 H, or CH-CHCO 2 R;
- (f) Z is N or CR 9 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a second aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl Of C 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , CO 2 H, CO
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including
- OCH 3 OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1-6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR 1 , NH 2 , NHR 1 , NR' 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , CO 2 H, CO 2 R
- R 9 is an H, F, OH, OR 1 , NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a third aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR 2 , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , CO 2 H, CO 2 R'
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl Of C 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F,
- (f) Z is N or CR 9 ;
- R 9 is an H, F, OH, OR', NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R 1 comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a fourth aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, T) lower alkenyl Of C 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, T) lower alkoxy OfC 1 -C 6 , CO 2 H,
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 ,
- (f) Z is N or CR 9 ;
- R 9 is an H, F, OH, OR', NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms;
- a fifth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR 1 , NR' 2 , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , CO 2 H
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR, NH 2 , NHR', NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C 6 , CO 2 H, CO 2 R', CONH 2
- (f) Z is N or CR 9 ;
- R 9 is an H, F, OH, OR', NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a sixth aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, heterocycle, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR 2 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of Ci- C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, Ci -I0 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR', NH 2 , NHR', NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C 1 -C 6 , CO 2 H, CO 2 R', CON
- R 9 is an H, F, OH, OR 1 , NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NRZ 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a seventh aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR 2 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, C 1-10 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H
- R 3 is CH 3 ;
- R 7 and R 8 are independently H, F, Cl, Br, I, OH, OR, such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy, SH, SR, NH 2 , NHR', NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl OfC 2 -C 6 , halogenated (F, Cl, Br, I) lower alkenyl of C 2 - C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C 6 , CO 2 H, CO 2 R', CONH 2
- (f) Z is N or CR 9 ;
- R 9 is an H, F, OH, OR', NH 2 , NHR', NR' 2 , lower alkyl, halogenated (F, Cl, Br, I) lower alkyl;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- An eighth aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, C 1-10 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H
- R 3 is CH 3 ;
- X is F
- R 7 is OR 1 , such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy and R 8 is NH 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a ninth aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H or lower alkyl
- R 2 is H
- R 3 is CH 3 ;
- R 7 is OR', such as alkoxy, aryloxy, benzyloxy, substituted aryloxy, and substituted benzyloxy and R is NH 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a tenth aspect of the third embodiment is directed to a compound represented by formula 1-3
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, C 1-10 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2- I 0 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H
- R 3 is CH 3 ;
- R 7 is NHR', NR' 2 , NHR' 2 + , or NR' 3 + and R 8 is NH 2 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- An eleventh aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is CH 3 or 'Pr; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 and R 8 are independently H, F, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NR' 2 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , or OR', such as OMe, OEt, OBn, and (f) Z is N; wherein R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or
- a twelfth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is CH 3 or 1 Pr; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is -N(-CH 2 CH 2 CH 2 -) (azetidin-1-yl); and R 8 is NH 2 ; and (f) Z is
- a thirteenth aspect of the third embodiment is directed to a compound represented by formula I wherein (a) R 1 is CH 3 or ! Pr; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is OEt and R 8 is NH 2 ; and (f) Z is N.
- a fourteenth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is CH 3 or 'Pr; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is OEt and R 8 is NH 2 ; and (f) Z is N.
- a fifteenth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is CH 3 ; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is -N(-CH 2 CH 2 CH 2 -) (azetidin-1-yl); and R 8 is NH 2 ; and (f) Z is N.
- a sixteenth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is CH 3 ; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is OEt and R 8 is NH 2 ; and (f) Z is N.
- a seventeenth aspect of the third embodiment is directed to a compound represented by formula 1-3 wherein (a) R 1 is 'Pr; (b) R 2 is H; (c) R 3 is CH 3 ; (d) X is F; (e) R 7 is OEt and R 8 is NH 2 ; and (f) Z is N.
- An N th aspect of the third embodiment is directed to a compound as exemplified below.
- a fourth embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula d above, wherein R 1 , R 2 , R 3 , X, and Y are defined in the Summary of the Invention section above.
- the first aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR, NH 2 , NHR', NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl Of C 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the second aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR, SH, SR, NH 2 , NHR 1 , NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including
- OCH 3 OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F; and (d) X is H, OH, F, OMe, NH 2 , or N 3 ;
- R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the third aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR 1 , NR 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the fourth aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR 2 , NHR' 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the fifth aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR 1 , NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkyl
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the sixth aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, C 1-10 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the seventh aspect of the fourth embodiment is directed to a compound represented by formula 1-4
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NRZ 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 , wherein R' is an optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxyalkyl, which includes, but is not limited to, C 1-10 alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxyalkyl;
- R 2 is H
- R 3 is CH 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a fifth embodiment of the invention is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, U, and mm above, wherein R , R , R , X, and Y are defined in the Summary of the Invention section above.
- the first aspect of the fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR 1 , NH 2 , NHR 1 , NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alky
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the second aspect of the fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl Of C 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the third aspect of fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR, SH, SR, NH 2 , NHR 1 , NR 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including
- OCH 3 OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R 1 comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the fourth aspect of fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c 1 , d 1 , e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R' comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R are joined to form a heterocycle comprising at least two carbon atoms.
- the fifth aspect of the fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the sixth aspect of the fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c 1 , d', e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR, NH 2 , NHR', NR' 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ; and (d) X is F;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the seventh aspect of the fifth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures c', d f , e, f, g, h, i, j, k, 1, m, n, o, p, q, r, s, t, u, v, w, x, y, z, aa, bb, cc, dd, ee, ff, gg, hh, ii, jj, kk, 11, and mm above,
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR, NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H
- R 3 is CH 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- a sixth embodiment of the invention is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above, wherein R 1 , R 2 , R 3 , X, and Y are defined in the Summary of the Invention section above.
- the first aspect of the sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR, NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1-6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR' 2 + each R 1 comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the second aspect of the sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR 1 , NH 2 , NHR', NR' 2 , NHR 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl Of C 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , or F;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance OfNR 2 or NHR 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the third aspect of sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR, SH, SR, NH 2 , NHR, NR 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including
- OCH 3 OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1-6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- X is H, OH, F, OMe, NH 2 , or N 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the fourth aspect of sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR', SH, SR', NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ €H, halogenated (F, Cl, Br, I) lower alkynyl OfC 2 -C 6 , lower alkoxy Of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alk
- R 2 is H, a lower alkyl, cyano (CN), vinyl, O-(lower alkyl), including OCH 3 , OCH 2 CH 3 , hydroxyl lower alkyl, i.e., -(CH 2 ) P OH, where p is 1 -6, including hydroxyl methyl (CH 2 OH), fluoromethyl (CH 2 F), azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 , CH 2 F, CHF 2 , CF 3 ;
- R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R 1 comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the fifth aspect of the sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, n-alkyl, branched alkyl, cycloalkyl, alkaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR', NH 2 , NHR 1 , NR' 2 , NHR 2 + , NR 3 + , heterocycle, lower alkyl, halogenated (F, Cl, Br, I), halogenated (F, Cl, Br, I) lower alkenyl OfC 2 -C 6 , lower alkynyl OfC 2 -C 6 such as C ⁇ CH, halogenated (F, Cl, Br, I) lower alkynyl of C 2 -C 6 , lower alkoxy of C 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy of C
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I;
- R 3 is CH 3 ;
- R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR 2 or NHR 2 + each R comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR 3 + each R comprises at least one C atom which are independent of one another or each R comprises at least one C atom in which at least two R' are joined to form a heterocycle comprising at least two carbon atoms.
- the sixth aspect of the sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above,
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR 1 , NH 2 , NHR', NR' 2 , NHR' 2 + , NR' 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy Of C 1 -C 6 ;
- R 2 is H, -CH 3 , cyano (CN), vinyl, -OCH 3 , -CH 2 OH, -CH 2 F, azido (N 3 ), CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , F, Cl, Br, or I
- R 3 is CH 3 ;
- X is F; wherein R' is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R 1 comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R comprises at least one C atom which are independent of one another or each R' comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- the seventh aspect of the sixth embodiment is directed to a compound represented by formula I in which the Base is a structure selected from among the structures ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al, am, an, ao, ap, aq, ar, as, at, av, au, ax, ay, az, ba, be, bd, be, bf, bg, bh, bi, bj, and bk, depicted above, wherein
- R 1 is H, lower alkyl, lower alkylaryl, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of H, F, Cl, Br, I, OH, OR 1 , SH, SR 1 , NH 2 , NHR 1 , NR' 2 , NHR 2 + , NR ! 3 + , heterocycle, lower alkoxy OfC 1 -C 6 , halogenated (F, Cl, Br, I) lower alkoxy OfC 1 -C 6 ;
- R 2 is H
- R 3 is CH 3 ;
- X is F; wherein R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkynyl, an optionally substituted alkenyl, or an optionally substituted acyl, an optionally substituted alkoxyalkyl, where for the instance of NR' 2 or NHR' 2 + each R' comprise at least one C atom that is independent of one another or are joined to form a heterocycle comprising at least two carbon atoms, and where for the instance of NR' 3 + each R' comprises at least one C atom which are independent of one another or each R 1 comprises at least one C atom in which at least two R 1 are joined to form a heterocycle comprising at least two carbon atoms.
- a seventh embodiment of the present invention is directed to a compound represented by formula I' its stereoisomers, salts, pharmaceutically acceptable salts, hydrates, solvates, crystalline, or metabolite forms thereof obtained by hydrolysis of the compound represented by formula I, followed by subsequent phosphorylation of the resultant hydrolysis product of the compound of formula F:
- Z is R 1 , HO— P-O-P- , or HO— P-0-p-O-P— HO OH HO OH OH OH
- R 7 is as defined herein above.
- An eighth embodiment of the present invention is directed to a composition for the treatment of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, or equivalent medium and a compound, that is intended to include its salts (acid or basic addition salts), hydrates, solvates, and crystalline forms can be obtained, represented by formula I.
- formulation of the eighth embodiment can contain any of the compounds contemplated in any of the aspects of the first, second, third, fourth, fifth, sixth, and seventh embodiments either alone or in combination with another compound of the present invention.
- the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
- Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
- Compounds of the present invention are efficacious when administered by suppository administration, among other routes of administration.
- the most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.
- a compound or compounds of the present invention, as well as their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
- the pharmaceutical compositions and unit dosage forms maybe comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration.
- a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
- preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
- excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
- the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
- a “pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
- pharmaceutically acceptable salt of a compound as used herein means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like
- Solid form preparations include, for example, powders, tablets, pills, capsules, suppositories, and dispersible granules.
- a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component, hi tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- solid formulations are exemplified in EP 0524579; US 6,635,278; US 2007/0099902; US 7,060,294; US 2006/0188570; US 2007/0077295; US 2004/0224917; US 7,462,608; US 2006/0057196; US 6,267,985; US 6,294,192; US 6,569,463; US 6,923,988; US 2006/0034937; US 6,383,471; US 6,395,300; US 6,645,528; US 6,932,983; US 2002/0142050; US 2005/0048116; US 2005/0058710; US 2007/0026073; US 2007/0059360; and US 2008/0014228, each of which is incorporated by reference.
- Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Examples of liquid formulation are exemplified in U.S. Patent Nos. 3,994,974; 5,695,784; and 6,977,257.
- Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
- Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
- the compounds of the present invention may be formulated for administration as suppositories.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
- the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania, which is hereby incorporated by reference.
- a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
- the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (e.g., salt formulation), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
- the compound of formula I may be independently formulated in conjunction with liposomes or micelles.
- liposomes it is contemplated that the purified compounds can be formulated in a manner as disclosed in U.S. Patent Nos. 5,013,556; U.S.
- a ninth embodiment of the present invention is directed to a use of the compound represented by formula I in the manufacture of a medicament for the treatment of any condition the result of an infection by any one of the following viral agents: hepatitis C virus, West Nile virus, yellow fever virus, degue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus and Japanese encephalitis virus.
- the term “medicament” means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising the compound of formula I. It is contemplated that the compound of the use of the compound represented by formula I in the manufacture of a medicament for the treatment of any of the antiviral conditions disclosed herein of the night embodiment can be any of the compounds contemplated in any of the aspects of the first, second, third, fourth, fifth, sixth, and seventh embodiments or those specifically exemplified, either alone or in combination with another compound of the present invention.
- a medicament includes, but is not limited to, any one of the compositions contemplated by the eighth embodiment of the present invention.
- a tenth embodiment of the present invention is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective amount of the compound represented by formula I to the subject.
- a first aspect of the tenth embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective of at least two compounds falling within the scope of the compound represented by formula I to the subject.
- a second aspect of the tenth embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of at least two compounds falling within the scope of the compound represented by formula I to the subject.
- a subject in need thereof is one that has any condition the result of an infection by any of the viral agents disclosed herein, which includes, but is not limited to, hepatitis C virus, West Nile virus, yellow fever virus, degue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, flaviviridae viruses or pestiviruses or hepaciviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.
- the viral agents disclosed herein includes, but is not limited to, hepatitis C virus, West Nile virus, yellow fever virus, degue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, flaviviridae viruses or pestiviruses or hepaciviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.
- subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the tenth embodiment can be any of the compounds contemplated in any of the aspects of the first, second, third, fourth, fifth, sixth, and seventh embodiments or those specifically recited in the tables above, either alone or in combination with another compound of the present invention.
- terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
- the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
- a daily dosage of between about 0.001 and about 10 g including all values in between, such as 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.050, 0.075, 0.1, 0.125, 0.150, 0.175, 0.2, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should be appropriate in monotherapy and/or in combination therapy.
- a particular daily dosage is between about 0.01 and about 1 g per day, including all incremental values of 0.01 g (i.e., 10 mg) in between, a preferred daily dosage about 0.01 and about 0.8 g per day, more preferably about 0.01 and about 0.6 g per day, and most preferably about 0.01 and about 0.25 g per day, each of which including all incremental values of 0.01 g in between.
- treatment is initiated with a large initial "loading dose" to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection.
- One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
- Therapeutic efficacy can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively the therapeutic effectiveness may be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized.
- serum proteins e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleos
- a third aspect of the tenth embodiment to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering to the subject a therapeutically effective of a compound represented by formula I and a therapeutically effective amount of another antiviral agent; wherein the administration is concurrent or alternative.
- the time between alternative administration can range between 1-24 hours, which includes any subrange in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
- HCV NS3 protease inhibitors see WO 2008010921, WO 2008010921, EP 1881001, WO 2007015824, WO 2007014925, WO 2007014926, WO 2007014921, WO 2007014920, WO 2007014922, US 2005267018, WO 2005095403, WO 2005037214, WO 2004094452, US 2003187018, WO 200364456, WO 2005028502, and WO 2003006490); HCV NS5B Inhibitors (see US 2007275947, US20072759300, WO2007095269, WO 2007092000, WO 2007076034, WO 200702602, US 2005-98125, WO 2006093801, US 2006166964, WO 2006065590, WO 2006065335, US 2006040927, US 2006040890, WO 2006020082, WO 2006012078, WO 2005123087
- HCV NS4 Inhibitors see WO 2007070556 and WO 2005067900
- HCV NS5a Inhibitors see US 2006276511, WO 2006120252, WO 2006120251, WO 2006100310, WO 2006035061
- Toll-like receptor agonists see WO 2007093901
- other inhibitors see WO 2004035571, WO 2004014852, WO 2004014313, WO 2004009020, WO 2003101993, WO 2000006529.
- a fourth aspect of the tenth embodiment to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of a compound represented by formula I and another antiviral agent to the subject.
- the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, and 23 hours.
- the another antiviral agent such as interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ , ribavirin, levovirin, viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor.
- the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound.
- the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives.
- Concurrent administration as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
- references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions.
- treatment also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
- An eleventh embodiment of the present invention is directed to a process for preparing the compound of formula I, which comprises reacting III with R 1 OP(NR 2 ) 2 , and then oxidizing II to form I according to the following scheme
- R 1 , R 2 , R 3 , X, and Base are defined above;
- R 1 OP(NR 2 ) 2 is a dialkylamino-R 1 phosphite
- B is a Br ⁇ nsted base
- [O] is an oxidant, such as, for example, m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, NO 2 /N 2 O 4 , etc.
- a twelfth embodiment of the present invention is directed to a product, I, prepared by a process which comprises reacting III with R 1 OP(NR 2 ) 2 , and then oxidizing II according to the following scheme
- R , R , R , X, and Base are defined above;
- R 1 OP(NR 2 ) 2 is a dialkylamino-alkylphosphite
- B is a Br ⁇ nsted base
- [O] is an oxidant, such as, for example, m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, NO 2 /N 2 O 4 , etc.
- the nucleoside analog is made by conventional procedures disclosed in any one of U.S. Published Application Nos. 2005/0009737, 2006/0199783,
- cyclic phosphates can also be prepared via an alternate route described below.
- Nucleoside III can be reacted with POCl 3 to produce the nucleoside mono phosphate, which upon cyclization and dehydration would give cyclic phosphate.
- bases such as TEA
- DIEA in solvents such as DMF, acetonitrile etc
- coupling with alcohols in the presence of reagents like DCC or EDC or MSNT would give desired products, using the procedures disclosed in, for example, Beres et al. J. Med. Chem. 1986, 29, 1243-1249 and WO 2007/027248 both of which are incorporated by reference, and as depicted in the following scheme.
- Compound (7) can be obtained by a process disclosed at page 5 in U.S. Published Application No. 2008/0139802 (which corresponds to WO 2008/045419), at pages 11 - 13 in WO 2006/012440, and at pages 20-22 and 30-31 in WO 2006/031725, each of which is hereby incorporated by reference.
- the preferred approach became the Sjy2 type reaction using a halo-sugar and a salt of the purine base. Again, the challenge of this approach was how to obtain an ex halo-sugar stereospecifically in high yield to take advantage the inversion of configuration expected with S # 2 type reactions.
- a typical method treats an anomeric mixture of the 1-O-acetate of a sugar with HCl or HBr in acetic acid. However, this method resulted in production of unfavorable anomeric mixtures.
- N-chlorosuccinimide produced an ⁇ -chlorosugar (9) in a stereospecific manner in almost quantitative yield.
- N-bromosuccinimide N-bromosuccinimide
- HBr HBr in acetic acid
- PPh 3 triphenylphosphine
- CBr 4 carbon tetrabromide
- the iodosugar (11) was prepared in a similar manner, which can be coupled with the purine to produce the key intermediate (12).
- the anomeric mixture was isolated in 63% yield in a ratio of 14: 1 ⁇ lou
- the /3-anomer (12) could be selectively crystallized out from a methanolic solution to give the pure desired ⁇ - anomer (6) in 55% yield from the bromosugar (10).
- the residue was purified by plug column (2.2 kg of 40-63 micron silica gel, packed in a 6 L sintered glass funnel, 22 cm length of silica gel, diameter 15 cm) using suction and a step-gradient of 5%, 10%, 20%, and 30% ethyl acetate in hexanes -ca 5 L of each).
- the product containing fractions were combined and concentrated under reduced pressure to a colorless, very thick liquid (310.4 g).
- the liquid slowly solidified after adding crystalline beta product as seeds (ca 100 mg spread out) under vacuum (0.2 mmHg) at 5O 0 C.
- the process of solidification was complete in 20 hours at 5O 0 C with or without vacuum.
- the white solid thus collected (293.8 g, 77%) has a mp of 79-80 0 C and ratio of ⁇ /ais 20:1 based on NMR.
- the reaction was judged to be >95% complete by TLC (RfS 0.61 (a), 0.72 ( ⁇ ), 0.36 lactol; 20% EtOAc in hexanes).
- the reaction solution was immediately transferred to a vessel containing 23O g of flash chromatography grade silica gel (40-63 microns).
- the stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glass Buchner funnel.
- the bromide solution was added to the purine base suspension over 1 min at ambient temperature.
- the 5L flask was rinsed with acetonitrile (2x1 L) to transfer bromide completely to the reaction mixture.
- the mixture was heated gradually to 50°C over 2 h with a heating mantle and controller, and stirred for 20 h.
- the reaction was almost complete as shown by TLC beta (R/ 0.28, 30% EtOAc in hexanes).
- the reaction was quenched by the addition of sat. NH 4 Cl (200 mL) to form a suspension.
- the suspended solid 1 was removed by filtration through a 3 cm pad of Celite in a 2.5 L porcelain Buchner funnel. The solid was washed with toluene (3x100 mL).
- the combined filtrate was neutralized by adding 6 N HCl solution until pH 7 (approx 220 mL).
- the mixture was concentrated under reduced pressure. When the volume of mixture was reduced to about one-third volume, additional precipitated solid was removed by filtration in a similar manner.
- the filtrate was further concentrated to a volume of about 800 mL.
- the product mixture foam was dissolved in methanol (700 mL) at ambient temperature. Upon standing, a solid slowly formed over 2 h. The suspension was cooled in a freezer to -5°C for 17 h. The resulting white solid was collected by filtration and washed with cold MeOH (-5 0 C, 3x60 mL) and ethyl ether (3x100 mL). The solid was dried under vacuum (0.2 mmHg, 24 h, ambient temp.) to afford 110.5 g of /3- ⁇ roduct with excellent de ( ⁇ /a 99.8:1 by HPLC). The filtrate was partially concentrated (ca. 400 mL) and then diluted with more MeOH (400 mL) while heating to 60°C.
- the reaction was quenched upon the addition of water (0.1 mL).
- the reaction solution was concentrated under reduced pressure and then the residue was triturated with ethyl acetate (5 mL).
- the resulting white precipitate was removed by filtration and the filtrate was concentrated under reduced pressure.
- the resulting intermediate cyclic phosphite residue was dissolved in acetonitrile (2 mL) and then treated with t-butyl hydroperoxide (70% in water, 0.25 mL) for 17 at ambient temperature. TLC indicated a complete reaction.
- the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography (Analogix using a gradient of 0 to 10% IPA in DCM). The product containing fractions were combined and concentrated under reduced pressure to a white solid, 80 mg (34% yield) as a mixture of two diastereomers -2:1.
- Example 41 was prepared by catalytic hydrogenation of Example 44 and in a similar way Example 45 was prepared from Example 48. Diastereomers of some of the compounds have been resolved, but where the absolute stereochemistry is not known, the same structures are provided.
- HCV replicon assay HCV replicon assay.
- HCV replicon RNA-containing Huh7 cells (clone A cells; Apath, LLC, St. Louis, Mo.) were kept at exponential growth in Dulbecco's modified Eagle's medium (high glucose) containing 10% fetal bovine serum, 4 mM L-glutamine and 1 mM sodium pyruvate, Ix nonessential amino acids, and G418 (1,000 ⁇ g/ml).
- Antiviral assays were performed in the same medium without G418. Cells were seeded in a 96-well plate at 1,500 cells per well, and test compounds were added immediately after seeding. Incubation time 4 days.
- Replicon RNA and an internal control (TaqMan rRNA control reagents; Applied Biosystems) were amplified in a single-step multiplex RT-PCR protocol as recommended by the manufacturer.
- the HCV primers and probe were designed with Primer Express software (Applied Biosystems) and covered highly conserved 5 '-untranslated region (UTR) sequences (sense, 5'-AGCCATGGCGTTAGTA(T)GAGTGT-S', and antisense, 5'-TTCCGCAGACCACTATGG-S'; probe, 5'-FAM- CCTCCAGGACCCCCCCTCCC-TAMRA-3').
- the threshold RT-PCR cycle of the test compound was subtracted from the average threshold RT-PCR cycle of the no-drug control ( ⁇ Ct ⁇ cv)- A ⁇ Ct of 3.3 equals a 1-log 10 reduction (equal to the 90% effective concentration [EC 90 ]) in replicon RNA levels.
- the cytotoxicity of the test compound could also be expressed by calculating the ⁇ Ct r RNA values.
- the ⁇ Ct specificity parameter could then be introduced ( ⁇ Ct ⁇ cv ⁇ ⁇ Ct r R NA ) > in which the levels of HCV RNA are normalized for the rRNA levels and calibrated against the no-drug control.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6068308P | 2008-06-11 | 2008-06-11 | |
US14036908P | 2008-12-23 | 2008-12-23 | |
US12/479,075 US8173621B2 (en) | 2008-06-11 | 2009-06-05 | Nucleoside cyclicphosphates |
PCT/US2009/046619 WO2009152095A2 (en) | 2008-06-11 | 2009-06-08 | Nucleoside cyclicphosphates |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2313422A2 true EP2313422A2 (en) | 2011-04-27 |
EP2313422B1 EP2313422B1 (en) | 2015-03-04 |
Family
ID=40974681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09763386.1A Active EP2313422B1 (en) | 2008-06-11 | 2009-06-08 | Nucleoside cyclicphosphates |
Country Status (19)
Country | Link |
---|---|
US (2) | US8173621B2 (en) |
EP (1) | EP2313422B1 (en) |
JP (2) | JP5749160B2 (en) |
KR (2) | KR101682494B1 (en) |
CN (1) | CN102119167A (en) |
AR (1) | AR072104A1 (en) |
AU (1) | AU2009257647C1 (en) |
BR (1) | BRPI0915484A2 (en) |
CA (1) | CA2727495C (en) |
CL (1) | CL2010001407A1 (en) |
CO (1) | CO6321272A2 (en) |
ES (1) | ES2536727T3 (en) |
IL (1) | IL209916A (en) |
MX (1) | MX2010013768A (en) |
PT (1) | PT2313422E (en) |
TW (1) | TW201002733A (en) |
UY (1) | UY31892A (en) |
WO (1) | WO2009152095A2 (en) |
ZA (1) | ZA201008829B (en) |
Families Citing this family (97)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
AU2003298658A1 (en) | 2002-11-15 | 2004-06-15 | Idenix (Cayman) Limited | 2'-branched nucleosides and flaviviridae mutation |
EP1633766B1 (en) | 2003-05-30 | 2019-03-06 | Gilead Pharmasset LLC | Modified fluorinated nucleoside analogues |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
TW201026715A (en) | 2008-12-23 | 2010-07-16 | Pharmasset Inc | Nucleoside phosphoramidates |
JP5793084B2 (en) * | 2008-12-23 | 2015-10-14 | ギリアド ファーマセット エルエルシー | Synthesis of purine nucleosides |
MX2011006890A (en) | 2008-12-23 | 2011-07-20 | Pharmasset Inc | Nucleoside analogs. |
CN102421293A (en) * | 2009-03-20 | 2012-04-18 | 艾丽奥斯生物制药有限公司 | Substituted nucleoside and nucleotide analogs |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI576352B (en) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | Nucleoside phosphoramidates |
PL3290428T3 (en) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
UY33310A (en) | 2010-03-31 | 2011-10-31 | Pharmasset Inc | ESTEREOSELECTIVE SYNTHESIS OF ASSETS CONTAINING PHOSPHORUS |
PT2552930E (en) | 2010-03-31 | 2015-11-17 | Gilead Pharmasset Llc | Crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1-(2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
US8940313B2 (en) | 2010-04-23 | 2015-01-27 | University Of Southern California | Tyrosine-based prodrugs of antiviral agents |
AP3584A (en) | 2010-09-22 | 2016-02-09 | Alios Biopharma Inc | Substituted nucleotide analogs |
US8877731B2 (en) | 2010-09-22 | 2014-11-04 | Alios Biopharma, Inc. | Azido nucleosides and nucleotide analogs |
CA2818853A1 (en) | 2010-11-30 | 2012-06-07 | Gilead Pharmasset Llc | 2'-spirocyclo-nucleosides for use in therapy of hcv or dengue virus |
EP2655392B1 (en) * | 2010-12-22 | 2018-04-18 | Alios Biopharma, Inc. | Cyclic nucleotide analogs |
EP2691409B1 (en) | 2011-03-31 | 2018-02-21 | Idenix Pharmaceuticals LLC. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2012154698A2 (en) | 2011-05-06 | 2012-11-15 | Mckenna Charles E | Method to improve antiviral activity of nucleotide analogue drugs |
TW201329096A (en) | 2011-09-12 | 2013-07-16 | Idenix Pharmaceuticals Inc | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
NZ623396A (en) | 2011-09-16 | 2016-07-29 | Gilead Pharmasset Llc | Methods for treating hcv |
TW201331221A (en) | 2011-10-14 | 2013-08-01 | Idenix Pharmaceuticals Inc | Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
CA3131037A1 (en) | 2011-11-30 | 2013-06-06 | Emory University | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
WO2013090420A2 (en) * | 2011-12-12 | 2013-06-20 | Catabasis Pharmaceuticals, Inc. | Fatty acid antiviral conjugates and their uses |
AU2012357940B2 (en) | 2011-12-20 | 2017-02-16 | Riboscience Llc | 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication |
EP2794630A4 (en) | 2011-12-22 | 2015-04-01 | Alios Biopharma Inc | Substituted phosphorothioate nucleotide analogs |
LT2794627T (en) | 2011-12-22 | 2019-01-10 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
CN104321333A (en) | 2012-03-21 | 2015-01-28 | 沃泰克斯药物股份有限公司 | Solid forms of a thiophosphoramidate nucleotide prodrug |
NZ630805A (en) | 2012-03-22 | 2016-01-29 | Alios Biopharma Inc | Pharmaceutical combinations comprising a thionucleotide analog |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013177188A1 (en) * | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
EA031301B1 (en) | 2012-05-22 | 2018-12-28 | Иденикс Фармасьютикалз Ллс | D-amino acid chemical compounds for treating liver diseases |
UY34824A (en) | 2012-05-25 | 2013-11-29 | Janssen R & D Ireland | NUCLEOSIDES OF URACILO SPYROOXETHANE |
RU2014149148A (en) * | 2012-05-29 | 2016-07-20 | Ф. Хоффманн-Ля Рош Аг | METHOD FOR PRODUCING 2-DEOXY-2-fluoro-2-methyl-d-ribofuranosyl compounds |
US9192621B2 (en) | 2012-09-27 | 2015-11-24 | Idenix Pharmaceuticals Llc | Esters and malonates of SATE prodrugs |
US10513534B2 (en) | 2012-10-08 | 2019-12-24 | Idenix Pharmaceuticals Llc | 2′-chloro nucleoside analogs for HCV infection |
US9457039B2 (en) | 2012-10-17 | 2016-10-04 | Merck Sharp & Dohme Corp. | 2′-disubstituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
WO2014059901A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | 2'-cyano substituted nucleoside derivatives and methods of use thereof for treatment of viral diseases |
US10723754B2 (en) | 2012-10-22 | 2020-07-28 | Idenix Pharmaceuticals Llc | 2′,4′-bridged nucleosides for HCV infection |
CN103804417B (en) * | 2012-11-13 | 2017-09-19 | 北京美倍他药物研究有限公司 | Anti-hepatic-B virus medicine |
JP2016501200A (en) | 2012-11-19 | 2016-01-18 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | 2-Alkynyl-substituted nucleoside derivatives for treating viral diseases |
US20140205566A1 (en) * | 2012-11-30 | 2014-07-24 | Novartis Ag | Cyclic nucleuoside derivatives and uses thereof |
WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
SI2935303T1 (en) | 2012-12-21 | 2021-08-31 | Janssen Biopharma, Inc. | 4'-fluoro-nucleosides, 4'-fluoro-nucleotides and analogs thereof for the treatment of hcv |
LT2950786T (en) | 2013-01-31 | 2020-03-10 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10034893B2 (en) * | 2013-02-01 | 2018-07-31 | Enanta Pharmaceuticals, Inc. | 5, 6-D2 uridine nucleoside/tide derivatives |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
US9309275B2 (en) | 2013-03-04 | 2016-04-12 | Idenix Pharmaceuticals Llc | 3′-deoxy nucleosides for the treatment of HCV |
WO2014160484A1 (en) | 2013-03-13 | 2014-10-02 | Idenix Pharmaceuticals, Inc. | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
CN105307662B (en) * | 2013-05-16 | 2019-06-04 | 里博科学有限责任公司 | 4 '-fluoro- 2 '-methyl substituted nucleoside derivates |
US20180200280A1 (en) | 2013-05-16 | 2018-07-19 | Riboscience Llc | 4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication |
US10005779B2 (en) | 2013-06-05 | 2018-06-26 | Idenix Pharmaceuticals Llc | 1′,4′-thio nucleosides for the treatment of HCV |
WO2014204831A1 (en) * | 2013-06-18 | 2014-12-24 | Merck Sharp & Dohme Corp. | Cyclic phosphonate substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
EP3027636B1 (en) | 2013-08-01 | 2022-01-05 | Idenix Pharmaceuticals LLC | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
MX2016002185A (en) | 2013-08-27 | 2016-06-06 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds. |
UA117375C2 (en) * | 2013-09-04 | 2018-07-25 | Медівір Аб | Hcv polymerase inhibitors |
JP6562908B2 (en) | 2013-10-11 | 2019-08-21 | ヤンセン バイオファーマ インク. | Substituted nucleosides, substituted nucleotides and analogs thereof |
WO2015077966A1 (en) * | 2013-11-28 | 2015-06-04 | Janssen R&D Ireland | Crystal form of nucleoside inhibitor of hcv |
US10683321B2 (en) | 2013-12-18 | 2020-06-16 | Idenix Pharmaceuticals Llc | 4′-or nucleosides for the treatment of HCV |
EP3131914B1 (en) | 2014-04-16 | 2023-05-10 | Idenix Pharmaceuticals LLC | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
US20170037078A1 (en) * | 2014-04-24 | 2017-02-09 | Cocrystal Pharma, Inc. | 2' -disubstituted nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
WO2016033164A1 (en) | 2014-08-26 | 2016-03-03 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
EP3212597A1 (en) * | 2014-10-31 | 2017-09-06 | Sandoz AG | Improved fluorination process |
US9718851B2 (en) | 2014-11-06 | 2017-08-01 | Enanta Pharmaceuticals, Inc. | Deuterated nucleoside/tide derivatives |
US9732110B2 (en) | 2014-12-05 | 2017-08-15 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
CN107427530B (en) | 2015-03-06 | 2020-09-08 | 阿堤亚制药公司 | β -D-2' -deoxy-2 ' α -fluoro-2 ' - β -C-substituted-2-modified-N for HCV treatment6-substituted purine nucleotides |
CN104817599B (en) * | 2015-03-20 | 2018-02-27 | 南京欧信医药技术有限公司 | A kind of synthetic method of 5 hydroxyl tetrahydrofuran derivative |
US10766917B2 (en) * | 2015-05-27 | 2020-09-08 | Idenix Pharmaceuticals Llc | Nucleotides for the treatment of cancer |
KR102630013B1 (en) | 2015-08-06 | 2024-01-25 | 키메릭스 인크. | Pyrrolopyrimidine nucleosides and analogues thereof useful as antiviral agents |
EP3454862A4 (en) | 2016-05-10 | 2020-02-12 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
CN109641874A (en) | 2016-05-10 | 2019-04-16 | C4医药公司 | C for target protein degradation3The glutarimide degron body of carbon connection |
BR112018073858A2 (en) | 2016-05-27 | 2019-02-26 | Gilead Sciences, Inc. | methods for treating hepatitis b virus infections using ns5a, ns5b or ns3 inhibitors |
US10202412B2 (en) | 2016-07-08 | 2019-02-12 | Atea Pharmaceuticals, Inc. | β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections |
WO2018013937A1 (en) | 2016-07-14 | 2018-01-18 | Atea Pharmaceuticals, Inc. | Beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-c-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection |
JP2019526596A (en) * | 2016-09-07 | 2019-09-19 | アテア ファーマシューティカルズ, インコーポレイテッド | 2'-substituted-N6-substituted purine nucleotides for RNA virus therapy |
KR102335193B1 (en) | 2017-02-01 | 2021-12-03 | 아테아 파마슈티컬즈, 인크. | Nucleotide hemi-sulfate salts for treating hepatitis C virus |
CN106810515A (en) * | 2017-02-06 | 2017-06-09 | 抚州市星辰药业有限公司 | The midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei |
EP3684374A4 (en) | 2017-09-21 | 2021-06-16 | Riboscience LLC | 4'-fluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication |
EP3684771A1 (en) | 2017-09-21 | 2020-07-29 | Chimerix, Inc. | MORPHIC FORMS OF 4-AMINO-7-(3,4-DIHYDROXY-5-(HYDROXYMETHYL)TETRAHYDROFURAN-2-YL)-2-METHYL-7H-PYRROLO[2,3-d]PYRIMIDINE-5-CARBOXAMIDE AND USES THEREOF |
CN109956975B (en) | 2017-12-22 | 2020-11-06 | 浙江柏拉阿图医药科技有限公司 | Liver delivery entecavir prodrug nucleoside cyclic phosphate ester compound and application thereof |
US11427550B2 (en) | 2018-01-19 | 2022-08-30 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
EP3773753A4 (en) | 2018-04-10 | 2021-12-22 | ATEA Pharmaceuticals, Inc. | Treatment of hcv infected patients with cirrhosis |
WO2020219464A1 (en) * | 2019-04-22 | 2020-10-29 | Ligand Pharmaceuticals, Inc. | Cyclic phosphate compounds |
TWI794742B (en) | 2020-02-18 | 2023-03-01 | 美商基利科學股份有限公司 | Antiviral compounds |
US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
CN111253454B (en) * | 2020-03-19 | 2022-03-08 | 江苏工程职业技术学院 | Preparation method of anti-hepatitis C drug sofosbuvir |
EP4121437A1 (en) | 2020-03-20 | 2023-01-25 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
CN115605492A (en) | 2020-04-21 | 2023-01-13 | 配体制药股份有限公司(Us) | Nucleotide prodrug compounds |
WO2022086958A1 (en) * | 2020-10-21 | 2022-04-28 | Ligand Pharmaceuticals Incorporated | Antiviral prodrug compounds |
EP4323362A1 (en) | 2021-04-16 | 2024-02-21 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
Family Cites Families (354)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2512572A (en) | 1950-06-20 | Substituted pteridines and method | ||
US2563707A (en) | 1947-12-12 | 1951-08-07 | American Cyanamid Co | Process for preparing pteridines |
GB768821A (en) | 1954-05-17 | 1957-02-20 | Gruenenthal Chemie | Novel products of the amino-piperidine-2, 6-dione series |
US3053865A (en) | 1958-03-19 | 1962-09-11 | Merck & Co Inc | Novel 16-alkyl and 16-alkylene steroids and processes |
US3097137A (en) | 1960-05-19 | 1963-07-09 | Canadian Patents Dev | Vincaleukoblastine |
US3104246A (en) | 1961-08-18 | 1963-09-17 | Roussel Uclaf | Process of preparation of beta-methasone |
FR1533151A (en) | 1962-05-18 | 1968-07-19 | Rhone Poulenc Sa | New antibiotic and its preparation |
US3300479A (en) * | 1965-08-05 | 1967-01-24 | Upjohn Co | Deazapurine riboside cyclic 3', 5'-phosphates and process therefor |
US3376380A (en) * | 1965-09-15 | 1968-04-02 | Sylvania Electric Prod | Synchronous demodulator with stabilized amplifiers and blanking |
NL6613143A (en) | 1965-09-21 | 1967-03-22 | ||
YU33730B (en) | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
US3480613A (en) | 1967-07-03 | 1969-11-25 | Merck & Co Inc | 2-c or 3-c-alkylribofuranosyl - 1-substituted compounds and the nucleosides thereof |
CH514578A (en) | 1968-02-27 | 1971-10-31 | Sandoz Ag | Process for the production of glucosides |
USRE29835E (en) | 1971-06-01 | 1978-11-14 | Icn Pharmaceuticals | 1,2,4-Triazole nucleosides |
US3798209A (en) * | 1971-06-01 | 1974-03-19 | Icn Pharmaceuticals | 1,2,4-triazole nucleosides |
US3849397A (en) | 1971-08-04 | 1974-11-19 | Int Chem & Nuclear Corp | 3',5'-cyclic monophosphate nucleosides |
US3994974A (en) | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
US3852267A (en) | 1972-08-04 | 1974-12-03 | Icn Pharmaceuticals | Phosphoramidates of 3{40 ,5{40 -cyclic purine nucleotides |
ZA737247B (en) | 1972-09-29 | 1975-04-30 | Ayerst Mckenna & Harrison | Rapamycin and process of preparation |
BE799805A (en) | 1973-05-23 | 1973-11-21 | Toyo Jozo Kk | NEW IMMUNOSUPPRESSOR AND ITS PREPARATION |
JPS535678B2 (en) | 1973-05-30 | 1978-03-01 | ||
US3991045A (en) | 1973-05-30 | 1976-11-09 | Asahi Kasei Kogyo Kabushiki Kaisha | N4 -acylarabinonucleosides |
US3888843A (en) | 1973-06-12 | 1975-06-10 | Toyo Jozo Kk | 4-carbamoyl-1-' -d-ribofuranosylimidazolium-5-olate |
SU508076A1 (en) | 1973-07-05 | 1976-10-05 | Институт По Изысканию Новых Антибиотиков Амн Ссср | Method for preparing carminomycin 1 |
GB1457632A (en) | 1974-03-22 | 1976-12-08 | Farmaceutici Italia | Adriamycins |
US3923785A (en) | 1974-04-22 | 1975-12-02 | Parke Davis & Co | (R)-3-(2-deoxy-{62 -D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo{8 4,5-d{9 {8 1,3{9 diazepin-8-ol |
GB1467383A (en) | 1974-06-12 | 1977-03-16 | Farmaceutici Italia | Daunomycin analogues |
US4199574A (en) | 1974-09-02 | 1980-04-22 | Burroughs Wellcome Co. | Methods and compositions for treating viral infections and guanine acyclic nucleosides |
GB1523865A (en) | 1974-09-02 | 1978-09-06 | Wellcome Found | Purine compunds and salts thereof |
GB1509875A (en) | 1976-06-14 | 1978-05-04 | Farmaceutici Italia | Optically active anthracyclinones and anthracycline glycosides |
SE445996B (en) | 1977-08-15 | 1986-08-04 | American Cyanamid Co | NEW ATRAKINO DERIVATIVES |
US4197249A (en) | 1977-08-15 | 1980-04-08 | American Cyanamid Company | 1,4-Bis(substituted-amino)-5,8-dihydroxyanthraquinones and leuco bases thereof |
US4203898A (en) | 1977-08-29 | 1980-05-20 | Eli Lilly And Company | Amide derivatives of VLB, leurosidine, leurocristine and related dimeric alkaloids |
US4210745A (en) | 1978-01-04 | 1980-07-01 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Procedure for the preparation of 9-β-D-arabinofuranosyl-2-fluoroadenine |
US4303785A (en) | 1978-08-05 | 1981-12-01 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Antitumor anthracycline antibiotics |
US4307100A (en) | 1978-08-24 | 1981-12-22 | Agence Nationale De Valorisation De La Recherche (Anvar) | Nor bis-indole compounds usable as medicaments |
DK160616C (en) | 1979-02-03 | 1991-09-02 | Zaidan Hojin Biseibutsu | PROCEDURE FOR PREPARING ANTHRACYCLINE DERIVATIVES OR ACID ADDITIONAL SALTS THEREOF |
JPS57109799A (en) * | 1980-12-26 | 1982-07-08 | Kikkoman Corp | Novel 2-halogeno-adenosine-3',5'-cyclic alkyl triphosphate, its preparation and antitumor agent containing the same |
GB2097788B (en) | 1981-04-03 | 1985-04-24 | Lilly Co Eli | Benzothiophene compounds and process for preparing them |
US4418068A (en) | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4355032B2 (en) | 1981-05-21 | 1990-10-30 | 9-(1,3-dihydroxy-2-propoxymethyl)guanine as antiviral agent | |
JPS5976099A (en) | 1982-10-22 | 1984-04-28 | Sumitomo Chem Co Ltd | Aminonaphthacene derivative and its preparation |
IT1155446B (en) | 1982-12-23 | 1987-01-28 | Erba Farmitalia | PROCEDURE FOR THE PURIFICATION OF ANTHRACYCLINONIC GLUCOSIDES BY SELECTIVE ADSOBMENT ON RESINS |
US4526988A (en) | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
JPS6019790A (en) | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | Novel camptothecin derivative |
DE3485225D1 (en) | 1983-08-18 | 1991-12-05 | Beecham Group Plc | ANTIVIRAL GUANINE DERIVATIVES. |
JPS6051189A (en) | 1983-08-30 | 1985-03-22 | Sankyo Co Ltd | Thiazolidine derivative and its preparation |
US4894366A (en) | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
US4760137A (en) | 1984-08-06 | 1988-07-26 | Brigham Young University | Method for the production of 2'-deoxyadenosine compounds |
CA1269659A (en) | 1984-08-06 | 1990-05-29 | Brigham Young University | Method for the production of 2'-deoxyadenosine compounds |
US5077056A (en) | 1984-08-08 | 1991-12-31 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
US5736155A (en) * | 1984-08-08 | 1998-04-07 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
NL8403224A (en) * | 1984-10-24 | 1986-05-16 | Oce Andeno Bv | DIOXAPHOSPHORINANS, THEIR PREPARATION AND THE USE FOR SPLITTING OF OPTICALLY ACTIVE COMPOUNDS. |
DK173350B1 (en) | 1985-02-26 | 2000-08-07 | Sankyo Co | Thiazolidine derivatives, their preparation and pharmaceutical composition containing them |
US5223263A (en) | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
US4724232A (en) | 1985-03-16 | 1988-02-09 | Burroughs Wellcome Co. | Treatment of human viral infections |
CS263951B1 (en) | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
GR861255B (en) | 1985-05-15 | 1986-09-16 | Wellcome Found | Therapeutic nucleosides |
US5246937A (en) | 1985-09-18 | 1993-09-21 | Beecham Group P.L.C. | Purine derivatives |
US4751221A (en) | 1985-10-18 | 1988-06-14 | Sloan-Kettering Institute For Cancer Research | 2-fluoro-arabinofuranosyl purine nucleosides |
US4797285A (en) * | 1985-12-06 | 1989-01-10 | Yissum Research And Development Company Of The Hebrew University Of Jerusalem | Lipsome/anthraquinone drug composition and method |
NZ219974A (en) | 1986-04-22 | 1989-08-29 | Goedecke Ag | N-(2'-aminophenyl)-benzamide derivatives, process for their preparation and their use in the control of neoplastic diseases |
FR2601675B1 (en) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US4753935A (en) | 1987-01-30 | 1988-06-28 | Syntex (U.S.A.) Inc. | Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions |
US5154930A (en) | 1987-03-05 | 1992-10-13 | The Liposome Company, Inc. | Pharmacological agent-lipid solution preparation |
US4923986A (en) | 1987-03-09 | 1990-05-08 | Kyowa Hakko Kogyo Co., Ltd. | Derivatives of physiologically active substance K-252 |
GB8719367D0 (en) | 1987-08-15 | 1987-09-23 | Wellcome Found | Therapeutic compounds |
US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
US4880784A (en) | 1987-12-21 | 1989-11-14 | Brigham Young University | Antiviral methods utilizing ribofuranosylthiazolo[4,5-d]pyrimdine derivatives |
US5130421A (en) | 1988-03-24 | 1992-07-14 | Bristol-Myers Company | Production of 2',3'-dideoxy-2',3'-didehydronucleosides |
GB8815265D0 (en) | 1988-06-27 | 1988-08-03 | Wellcome Found | Therapeutic nucleosides |
IL91664A (en) * | 1988-09-28 | 1993-05-13 | Yissum Res Dev Co | Ammonium transmembrane gradient system for efficient loading of liposomes with amphipathic drugs and their controlled release |
US6132763A (en) | 1988-10-20 | 2000-10-17 | Polymasc Pharmaceuticals Plc | Liposomes |
JPH02180894A (en) * | 1988-11-21 | 1990-07-13 | Syntex Usa Inc | Antiviral agent |
US5705363A (en) * | 1989-03-02 | 1998-01-06 | The Women's Research Institute | Recombinant production of human interferon τ polypeptides and nucleic acids |
US5277914A (en) * | 1989-03-31 | 1994-01-11 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
US5549910A (en) | 1989-03-31 | 1996-08-27 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
US5077057A (en) | 1989-04-05 | 1991-12-31 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
US5411947A (en) * | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
US5194654A (en) * | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
US5225212A (en) | 1989-10-20 | 1993-07-06 | Liposome Technology, Inc. | Microreservoir liposome composition and method |
US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5463092A (en) | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
GB8927913D0 (en) | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Amino acid derivatives |
US5026687A (en) | 1990-01-03 | 1991-06-25 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds |
US5041246A (en) | 1990-03-26 | 1991-08-20 | The Babcock & Wilcox Company | Two stage variable annulus spray attemperator method and apparatus |
CA2079912C (en) | 1990-04-06 | 2000-07-11 | Gregory Reyes | Hepatitis c virus epitopes |
US5091188A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
RU2084223C1 (en) | 1990-05-18 | 1997-07-20 | Хехст АГ | Use of isoxazole-4-carboxylic acid amides and hydroxyalkylidenecyanoacetic acid amides |
US6060080A (en) | 1990-07-16 | 2000-05-09 | Daiichi Pharmaceutical Co., Ltd. | Liposomal products |
JP2599492B2 (en) | 1990-08-21 | 1997-04-09 | 第一製薬株式会社 | Manufacturing method of liposome preparation |
US5372808A (en) | 1990-10-17 | 1994-12-13 | Amgen Inc. | Methods and compositions for the treatment of diseases with consensus interferon while reducing side effect |
US5206244A (en) | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
US5149794A (en) | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
US5543389A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5256641A (en) | 1990-11-01 | 1993-10-26 | State Of Oregon | Covalent polar lipid-peptide conjugates for immunological targeting |
US5925643A (en) | 1990-12-05 | 1999-07-20 | Emory University | Enantiomerically pure β-D-dioxolane-nucleosides |
JP3008226B2 (en) | 1991-01-16 | 2000-02-14 | 第一製薬株式会社 | Hexacyclic compounds |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
IE920754A1 (en) | 1991-03-08 | 1992-09-09 | Univ Vermont | 6,9 BIS(SUBSTITUTED-AMINO) BENZO[g]-ISOQUINOLINE-5,10-DIONES |
US5595732A (en) | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
US5157027A (en) | 1991-05-13 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Bisphosphonate squalene synthetase inhibitors and method |
NZ243567A (en) | 1991-07-22 | 1995-04-27 | Bristol Myers Squibb Co | Pharmaceutical oral formulation of a dideoxy purine nucleoside comprising the nucleoside together with a water-insoluble antacid buffering composition |
US5554728A (en) | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
GB9116601D0 (en) | 1991-08-01 | 1991-09-18 | Iaf Biochem Int | 1,3-oxathiolane nucleoside analogues |
TW224053B (en) | 1991-09-13 | 1994-05-21 | Paul B Chretien | |
DE4200821A1 (en) | 1992-01-15 | 1993-07-22 | Bayer Ag | TASTE-MASKED PHARMACEUTICAL AGENTS |
US5676942A (en) | 1992-02-10 | 1997-10-14 | Interferon Sciences, Inc. | Composition containing human alpha interferon species proteins and method for use thereof |
US5405598A (en) * | 1992-02-24 | 1995-04-11 | Schinazi; Raymond F. | Sensitizing agents for use in boron neutron capture therapy |
JP3102945B2 (en) * | 1992-02-27 | 2000-10-23 | 財団法人野田産業科学研究所 | Hepatitis treatment |
US5610054A (en) * | 1992-05-14 | 1997-03-11 | Ribozyme Pharmaceuticals, Inc. | Enzymatic RNA molecule targeted against Hepatitis C virus |
US5256798A (en) | 1992-06-22 | 1993-10-26 | Eli Lilly And Company | Process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates |
US5426183A (en) | 1992-06-22 | 1995-06-20 | Eli Lilly And Company | Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
DE69311000T2 (en) | 1992-06-22 | 1997-11-27 | Lilly Co Eli | Process for the preparation of 1-halogen-2-deoxy-2,2-difluoro-D-ribofuranosyl derivatives enriched with alpha anomers |
US5719147A (en) | 1992-06-29 | 1998-02-17 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
CA2105112C (en) * | 1992-09-01 | 2005-08-02 | Thomas C. Britton | A process for anomerizing nucleosides |
US5484926A (en) | 1993-10-07 | 1996-01-16 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
GB9226729D0 (en) | 1992-12-22 | 1993-02-17 | Wellcome Found | Therapeutic combination |
CA2156394A1 (en) * | 1993-02-24 | 1994-09-01 | Jui H. Wang | Compositions and methods of application of reactive antiviral polymers |
US6180134B1 (en) * | 1993-03-23 | 2001-01-30 | Sequus Pharmaceuticals, Inc. | Enhanced ciruclation effector composition and method |
AU688344B2 (en) | 1993-07-19 | 1998-03-12 | Mitsubishi-Tokyo Pharmaceuticals, Inc. | Hepatitis C virus proliferation inhibitor |
FR2707988B1 (en) | 1993-07-21 | 1995-10-13 | Pf Medicament | New antimitotic derivatives of binary alkaloids of catharantus rosesus, process for their preparation and pharmaceutical compositions comprising them. |
US7375198B2 (en) | 1993-10-26 | 2008-05-20 | Affymetrix, Inc. | Modified nucleic acid probes |
US6156501A (en) | 1993-10-26 | 2000-12-05 | Affymetrix, Inc. | Arrays of modified nucleic acid probes and methods of use |
PT730470E (en) * | 1993-11-10 | 2002-08-30 | Enzon Inc | IMPROVED INTERFERENCE-POLYMER CONJUGATES |
DE4415539C2 (en) * | 1994-05-03 | 1996-08-01 | Osama Dr Dr Med Omer | Plants with virustatic and antiviral effects |
IL129871A (en) | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
AU710074B2 (en) | 1994-06-22 | 1999-09-16 | Proligo Llc | Novel method of preparation of known and novel 2'-modified nucleosides by intramolecular nucleophilic displacement |
DE4432623A1 (en) * | 1994-09-14 | 1996-03-21 | Huels Chemische Werke Ag | Process for bleaching aqueous surfactant solutions |
US5738846A (en) * | 1994-11-10 | 1998-04-14 | Enzon, Inc. | Interferon polymer conjugates and process for preparing the same |
US5703058A (en) | 1995-01-27 | 1997-12-30 | Emory University | Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent |
US6391859B1 (en) | 1995-01-27 | 2002-05-21 | Emory University | [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides |
GB9505025D0 (en) | 1995-03-13 | 1995-05-03 | Medical Res Council | Chemical compounds |
GB9618952D0 (en) | 1996-09-11 | 1996-10-23 | Sandoz Ltd | Process |
US6504029B1 (en) | 1995-04-10 | 2003-01-07 | Daiichi Pharmaceutical Co., Ltd. | Condensed-hexacyclic compounds and a process therefor |
US5908621A (en) | 1995-11-02 | 1999-06-01 | Schering Corporation | Polyethylene glycol modified interferon therapy |
US5767097A (en) | 1996-01-23 | 1998-06-16 | Icn Pharmaceuticals, Inc. | Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes |
GB9602028D0 (en) | 1996-02-01 | 1996-04-03 | Amersham Int Plc | Nucleoside analogues |
US5980884A (en) | 1996-02-05 | 1999-11-09 | Amgen, Inc. | Methods for retreatment of patients afflicted with Hepatitis C using consensus interferon |
JP2000506010A (en) * | 1996-02-29 | 2000-05-23 | イミューソル インコーポレイテッド | Hepatitis C virus ribozyme |
US5633388A (en) * | 1996-03-29 | 1997-05-27 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5830905A (en) | 1996-03-29 | 1998-11-03 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5990276A (en) | 1996-05-10 | 1999-11-23 | Schering Corporation | Synthetic inhibitors of hepatitis C virus NS3 protease |
GB9609932D0 (en) | 1996-05-13 | 1996-07-17 | Hoffmann La Roche | Use of IL-12 and IFN alpha for the treatment of infectious diseases |
US5891874A (en) * | 1996-06-05 | 1999-04-06 | Eli Lilly And Company | Anti-viral compound |
US5837257A (en) | 1996-07-09 | 1998-11-17 | Sage R&D | Use of plant extracts for treatment of HIV, HCV and HBV infections |
US6214375B1 (en) * | 1996-07-16 | 2001-04-10 | Generex Pharmaceuticals, Inc. | Phospholipid formulations |
US5635517B1 (en) | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US5922757A (en) | 1996-09-30 | 1999-07-13 | The Regents Of The University Of California | Treatment and prevention of hepatic disorders |
US6174905B1 (en) | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
RU2182195C2 (en) * | 1996-10-04 | 2002-05-10 | Е.И. Дюпон Де Немур Энд Компани | Polyester-based fiber |
US6224903B1 (en) * | 1996-10-11 | 2001-05-01 | Sequus Pharmaceuticals, Inc. | Polymer-lipid conjugate for fusion of target membranes |
TW520297B (en) | 1996-10-11 | 2003-02-11 | Sequus Pharm Inc | Fusogenic liposome composition and method |
US6509320B1 (en) * | 1996-10-16 | 2003-01-21 | Icn Pharmaceuticals, Inc. | Purine L-nucleosides, analogs and uses thereof |
DE69721339T2 (en) | 1996-10-16 | 2004-01-22 | Ribapharm, Inc., Costa Mesa | MONOCYCLIC L-NUCLEOSIDES, ANALOGS AND THEIR APPLICATIONS |
US6455690B1 (en) | 1996-10-16 | 2002-09-24 | Robert Tam | L-8-oxo-7-propyl-7,8-dihydro-(9H)-guanosine |
ATE271063T1 (en) | 1996-10-16 | 2004-07-15 | Icn Pharmaceuticals | PURINE-L-NUCLEOSIDES, THEIR ANALOGUES AND USES |
IL119833A (en) * | 1996-12-15 | 2001-01-11 | Lavie David | Hypericum perforatum extracts for the preparation of pharmaceutical compositions for the treatment of hepatitis |
US5827533A (en) | 1997-02-06 | 1998-10-27 | Duke University | Liposomes containing active agents aggregated with lipid surfactants |
US20020127371A1 (en) | 2001-03-06 | 2002-09-12 | Weder Donald E. | Decorative elements provided with a circular or crimped configuration at point of sale or point of use |
US6004933A (en) | 1997-04-25 | 1999-12-21 | Cortech Inc. | Cysteine protease inhibitors |
FR2765191B1 (en) * | 1997-06-26 | 1999-08-20 | Cermex | METHOD AND MACHINE FOR AUTOMATICALLY BONDING A HEAT SHRINKABLE PLASTIC FILM ON THE BOTTOM OF AN OPEN BODY |
JP3963488B2 (en) * | 1997-06-30 | 2007-08-22 | メルツ ファーマ ゲゼルシャフト ミット ベシュレンクテル ハフツンク ウント コンパニー コマンディゲゼルシャフト アウフ アクチェン | 1-amino-alkylcyclohexane NMDA receptor antagonist |
JP3773148B2 (en) * | 1997-10-29 | 2006-05-10 | キッコーマン株式会社 | Ischemic disease prevention, treatment and organ preservative |
US6703374B1 (en) * | 1997-10-30 | 2004-03-09 | The United States Of America As Represented By The Department Of Health And Human Services | Nucleosides for imaging and treatment applications |
WO1999037753A1 (en) | 1998-01-23 | 1999-07-29 | Newbiotics, Inc. | Enzyme catalyzed therapeutic agents |
CN100349913C (en) | 1998-02-25 | 2007-11-21 | 埃莫里大学 | 2' -fluoro nucleosides |
US6787305B1 (en) | 1998-03-13 | 2004-09-07 | Invitrogen Corporation | Compositions and methods for enhanced synthesis of nucleic acid molecules |
US6475985B1 (en) | 1998-03-27 | 2002-11-05 | Regents Of The University Of Minnesota | Nucleosides with antiviral and anticancer activity |
GB9806815D0 (en) * | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
US20010014352A1 (en) | 1998-05-27 | 2001-08-16 | Udit Batra | Compressed tablet formulation |
US6726925B1 (en) * | 1998-06-18 | 2004-04-27 | Duke University | Temperature-sensitive liposomal formulation |
US6200598B1 (en) * | 1998-06-18 | 2001-03-13 | Duke University | Temperature-sensitive liposomal formulation |
US6320078B1 (en) | 1998-07-24 | 2001-11-20 | Mitsui Chemicals, Inc. | Method of producing benzamide derivatives |
US6323180B1 (en) | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
WO2000023453A1 (en) | 1998-10-16 | 2000-04-27 | Mercian Corporation | Crystallization of doxorubicin hydrochloride |
US6635278B1 (en) | 1998-12-15 | 2003-10-21 | Gilead Sciences, Inc. | Pharmaceutical formulations |
US6294192B1 (en) | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6267985B1 (en) | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
US6383471B1 (en) | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
US7919119B2 (en) | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
CN1079473C (en) | 1999-05-31 | 2002-02-20 | 李岭群 | Coupling rib for pre-fabricated beam |
AU5905400A (en) | 1999-07-14 | 2001-02-05 | Board Of Regents, The University Of Texas System | Methods and compositions for delivery and retention of active agents to lymph nodes |
WO2001034618A2 (en) * | 1999-11-12 | 2001-05-17 | Pharmasset Limited | Synthesis of 2'-deoxy-l-nucleosides |
US20060034937A1 (en) * | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6495677B1 (en) | 2000-02-15 | 2002-12-17 | Kanda S. Ramasamy | Nucleoside compounds |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
US6787526B1 (en) | 2000-05-26 | 2004-09-07 | Idenix Pharmaceuticals, Inc. | Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides |
WO2001092282A2 (en) * | 2000-05-26 | 2001-12-06 | Idenix (Cayman) Limited | Methods and compositions for treating flaviviruses and pestiviruses |
FR2810322B1 (en) * | 2000-06-14 | 2006-11-10 | Pasteur Institut | COMBINATORY PRODUCTION OF NUCLEOTIDE AND NUCLEOTIDE ANALOGUES (XiTP) |
US6815542B2 (en) | 2000-06-16 | 2004-11-09 | Ribapharm, Inc. | Nucleoside compounds and uses thereof |
UA72612C2 (en) | 2000-07-06 | 2005-03-15 | Pyrido[2.3-d]pyrimidine and pyrimido[4.5-d]pyrimidine nucleoside analogues, prodrugs and method for inhibiting growth of neoplastic cells | |
US6680068B2 (en) * | 2000-07-06 | 2004-01-20 | The General Hospital Corporation | Drug delivery formulations and targeting |
SI2682397T1 (en) | 2000-07-21 | 2017-08-31 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
AR039558A1 (en) | 2000-08-21 | 2005-02-23 | Inspire Pharmaceuticals Inc | COMPOSITIONS AND METHOD FOR THE TREATMENT OF GLAUCOMA OR OCULAR HYPERTENSION |
US6897201B2 (en) | 2000-08-21 | 2005-05-24 | Inspire Pharmaceuticals, Inc. | Compositions and methods for the treatment of glaucoma or ocular hypertension |
US7018985B1 (en) * | 2000-08-21 | 2006-03-28 | Inspire Pharmaceuticals, Inc. | Composition and method for inhibiting platelet aggregation |
US6555677B2 (en) * | 2000-10-31 | 2003-04-29 | Merck & Co., Inc. | Phase transfer catalyzed glycosidation of an indolocarbazole |
EP2360166A1 (en) * | 2001-01-22 | 2011-08-24 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US7105499B2 (en) | 2001-01-22 | 2006-09-12 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
MY129350A (en) | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
GB0112617D0 (en) | 2001-05-23 | 2001-07-18 | Hoffmann La Roche | Antiviral nucleoside derivatives |
GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
WO2003000713A1 (en) | 2001-06-21 | 2003-01-03 | Glaxo Group Limited | Nucleoside compounds in hcv |
ATE349463T1 (en) | 2001-07-11 | 2007-01-15 | Vertex Pharma | BRIDGED BIZYCLIC SERINE PROTEASE INHIBITORS |
EP2335700A1 (en) | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
US6962991B2 (en) | 2001-09-12 | 2005-11-08 | Epoch Biosciences, Inc. | Process for the synthesis of pyrazolopyrimidines |
EP1432721A4 (en) | 2001-09-13 | 2008-02-20 | Bristol Myers Squibb Co | Process for the preparation of rebeccamycin and analogs thereof |
WO2003024461A1 (en) | 2001-09-20 | 2003-03-27 | Schering Corporation | Hcv combination therapy |
US7138376B2 (en) * | 2001-09-28 | 2006-11-21 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides |
ES2289161T3 (en) | 2001-11-02 | 2008-02-01 | Glaxo Group Limited | DERIVATIVES OF 4- (HETEROARIL OF 6 MEMBERS) -ACIL PIRROLIDINA AS HCV INHIBITORS. |
EP1448170A4 (en) * | 2001-11-27 | 2010-05-12 | Bristol Myers Squibb Co | Efavirenz tablet formulation having unique biopharmaceutical characteristics |
GB0129945D0 (en) | 2001-12-13 | 2002-02-06 | Mrc Technology Ltd | Chemical compounds |
WO2003063771A2 (en) | 2001-12-14 | 2003-08-07 | Pharmasset Ltd. | N4-acylcytosine nucleosides for treatment of viral iinfections |
WO2003051899A1 (en) | 2001-12-17 | 2003-06-26 | Ribapharm Inc. | Deazapurine nucleoside libraries and compounds |
WO2003055896A2 (en) | 2001-12-21 | 2003-07-10 | Micrologix Biotech Inc. | Anti-viral 7-deaza l-nucleosides |
WO2003062256A1 (en) | 2002-01-17 | 2003-07-31 | Ribapharm Inc. | 2'-beta-modified-6-substituted adenosine analogs and their use as antiviral agents |
US7070801B2 (en) | 2002-01-30 | 2006-07-04 | National Institute Of Advanced Industrial Science And Technology | Sugar-modified liposome and products comprising the liposome |
US6642204B2 (en) | 2002-02-01 | 2003-11-04 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
CA2370396A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
EP1476169B1 (en) | 2002-02-13 | 2013-03-20 | Merck Sharp & Dohme Corp. | Inhibiting orthopoxvirus replication with nucleoside compounds |
JP2005525358A (en) * | 2002-02-28 | 2005-08-25 | ビオタ インコーポレーティッド | Nucleotide mimetics and their prodrugs |
WO2003073989A2 (en) * | 2002-02-28 | 2003-09-12 | Biota, Inc. | Nucleoside 5'-monophosphate mimics and their prodrugs |
AU2003231766A1 (en) | 2002-04-26 | 2003-11-10 | Gilead Sciences, Inc. | Non nucleoside reverse transcriptase inhibitors |
AU2003241621A1 (en) * | 2002-05-24 | 2003-12-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides having modified nucleoside units |
ATE389656T1 (en) | 2002-06-04 | 2008-04-15 | Neogenesis Pharmaceuticals Inc | PYRAZOLO(1,5-A)PYRIMIDINE COMPOUNDS AS ANTIVIRAL AGENTS |
EP1511757B1 (en) * | 2002-06-07 | 2015-11-04 | Universitair Medisch Centrum Utrecht | New compounds for modulating the activity of exchange proteins directly activated by camp (epacs) |
AU2003248708A1 (en) | 2002-06-17 | 2003-12-31 | Isis Pharmaceuticals, Inc. | Oligomeric compounds that include carbocyclic nucleosides and their use in gene modulation |
CA2489552A1 (en) * | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
US7608600B2 (en) * | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
BR0305426A (en) | 2002-07-01 | 2004-08-24 | Upjohn Co | Hsv ns5b polymerase inhibitor compounds as well as pharmaceutical composition comprising the same |
BR0305259A (en) | 2002-07-01 | 2004-10-05 | Upjohn Co | Hcv ns5b polymerase inhibitors |
WO2004009020A2 (en) | 2002-07-24 | 2004-01-29 | Merck & Co., Inc. | Pyrrolopyrimidine thionucleoside analogs as antivirals |
EP1527082A2 (en) * | 2002-07-25 | 2005-05-04 | Micrologix Biotech, Inc. | Anti-viral 7-deaza d-nucleosides and uses thereof |
WO2004024095A2 (en) * | 2002-09-13 | 2004-03-25 | Idenix (Cayman) Limited | ß-L-2'-DEOXYNUCLEOSIDES FOR THE TREATMENT OF RESISTANT HBV STRAINS AND COMBINATION THERAPIES |
EP1554271A1 (en) | 2002-10-15 | 2005-07-20 | Rigel Pharmaceuticals, Inc. | Substituted indoles and their use as hcv inhibitors |
US20040229840A1 (en) | 2002-10-29 | 2004-11-18 | Balkrishen Bhat | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US7265152B2 (en) | 2002-11-01 | 2007-09-04 | Viropharma Incorporated | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases |
AU2003298658A1 (en) * | 2002-11-15 | 2004-06-15 | Idenix (Cayman) Limited | 2'-branched nucleosides and flaviviridae mutation |
TWI332507B (en) * | 2002-11-19 | 2010-11-01 | Hoffmann La Roche | Antiviral nucleoside derivatives |
KR20050109918A (en) * | 2002-12-12 | 2005-11-22 | 이데닉스 (케이만) 리미티드 | Process for the production of 2'-branched nucleosides |
US20060246130A1 (en) | 2003-01-14 | 2006-11-02 | Dahl Terrence C | Compositions and methods for combination antiviral therapy |
US7223785B2 (en) | 2003-01-22 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
AU2003225705A1 (en) | 2003-03-07 | 2004-09-30 | Ribapharm Inc. | Cytidine analogs and methods of use |
CN101415719A (en) | 2003-03-20 | 2009-04-22 | 微生物化学及药品有限公司 | Methods of manufacture of 2 -deoxy-beta-L-nucleosides |
US20040202993A1 (en) | 2003-04-10 | 2004-10-14 | Poo Ramon E. | Apparatus and method for organ preservation and transportation |
ATE490788T1 (en) | 2003-04-25 | 2010-12-15 | Gilead Sciences Inc | ANTIVIRAL PHOSPHONATE ANALOGUE |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
US7470724B2 (en) * | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7452901B2 (en) * | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
US20050261237A1 (en) | 2003-04-25 | 2005-11-24 | Boojamra Constantine G | Nucleoside phosphonate analogs |
US20040259934A1 (en) | 2003-05-01 | 2004-12-23 | Olsen David B. | Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds |
WO2004096210A1 (en) | 2003-05-01 | 2004-11-11 | Glaxo Group Limited | Acylated indoline and tetrahydroquinoline derivatives as hcv inhibitors |
US20040229839A1 (en) | 2003-05-14 | 2004-11-18 | Biocryst Pharmaceuticals, Inc. | Substituted nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
WO2004106356A1 (en) | 2003-05-27 | 2004-12-09 | Syddansk Universitet | Functionalized nucleotide derivatives |
EP1633766B1 (en) | 2003-05-30 | 2019-03-06 | Gilead Pharmasset LLC | Modified fluorinated nucleoside analogues |
GB0317009D0 (en) | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
CN1852915A (en) * | 2003-07-25 | 2006-10-25 | 艾登尼科斯(开曼)有限公司 | Purine nucleoside analogues for treating flaviviridae including hepatitis c |
DE602004029904D1 (en) | 2003-08-27 | 2010-12-16 | Biota Scient Management | NEW TRICYCLIC NUCLEOSIDES OR NUCLEOTIDES THAN THERAPEUTIC AGENTS |
CA2538791A1 (en) | 2003-09-18 | 2005-03-31 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
US20050148534A1 (en) | 2003-09-22 | 2005-07-07 | Castellino Angelo J. | Small molecule compositions and methods for increasing drug efficiency using compositions thereof |
US7491794B2 (en) | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
US7026339B2 (en) | 2003-11-07 | 2006-04-11 | Fan Yang | Inhibitors of HCV NS5B polymerase |
AU2005216971A1 (en) * | 2004-02-25 | 2005-09-09 | Government Of The United States Of America, As Represented By The Secretary Department Of Health And Human Services Office Of Technology Transfer | Methylation inhibitor compounds |
CN100384237C (en) | 2004-02-28 | 2008-04-23 | 鸿富锦精密工业(深圳)有限公司 | Volume adjustment set and method |
US8759317B2 (en) | 2004-03-18 | 2014-06-24 | University Of South Florida | Method of treatment of cancer using guanosine 3′, 5′ cyclic monophosphate (cyclic GMP) |
GB0408995D0 (en) | 2004-04-22 | 2004-05-26 | Glaxo Group Ltd | Compounds |
WO2006000922A2 (en) * | 2004-06-23 | 2006-01-05 | Idenix (Cayman) Limited | 5-aza-7-deazapurine derivatives for treating infections with flaviviridae |
EP1773355B1 (en) | 2004-06-24 | 2014-06-25 | Merck Sharp & Dohme Corp. | Nucleoside aryl phosphoramidates for the treatment of rna-dependent rna viral infection |
US7217523B2 (en) | 2004-07-02 | 2007-05-15 | Regents Of The University Of Minnesota | Nucleoside phosphoramidates and nucleoside phosphoramidases |
CN101023094B (en) | 2004-07-21 | 2011-05-18 | 法莫赛特股份有限公司 | Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives |
DE602005027466D1 (en) * | 2004-07-27 | 2011-05-26 | Gilead Sciences Inc | NUCLEOSIDE PHOSPHONATE CONJUGATES AS ANTI HIV MEDIUM |
US7153848B2 (en) | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
US7348425B2 (en) | 2004-08-09 | 2008-03-25 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
JP4624419B2 (en) * | 2004-08-23 | 2011-02-02 | エフ.ホフマン−ラ ロシュ アーゲー | Antiviral heterocyclic compounds |
ES2327252T3 (en) * | 2004-08-23 | 2009-10-27 | F. Hoffmann-La Roche Ag | 4'-AZIDO ANTIVIRAL NUCLEOSIDS. |
PL3109244T3 (en) | 2004-09-14 | 2019-09-30 | Gilead Pharmasset Llc | Preparation of 2'fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
AR052771A1 (en) | 2004-09-30 | 2007-04-04 | Tibotec Pharm Ltd | HCV INHIBITING BICYCLE PYRIMIDINS |
EP1814561A4 (en) | 2004-10-29 | 2012-12-19 | Biocryst Pharm Inc | Therapeutic furopyrimidines and thienopyrimidines |
WO2006063149A1 (en) | 2004-12-09 | 2006-06-15 | Regents Of The University Of Minnesota | Nucleosides with antiviral and anticancer activity |
GB0427123D0 (en) | 2004-12-11 | 2005-01-12 | Apv Systems Ltd | Food item coating apparatus and method |
WO2006063717A2 (en) | 2004-12-16 | 2006-06-22 | Febit Biotech Gmbh | Polymerase-independent analysis of the sequence of polynucleotides |
WO2006093801A1 (en) | 2005-02-25 | 2006-09-08 | Abbott Laboratories | Thiadiazine derivatives useful as anti-infective agents |
CN101142226A (en) | 2005-02-28 | 2008-03-12 | 健亚生物科技公司 | Tricyclic-nucleoside prodrugs for treating viral infections |
US8802840B2 (en) | 2005-03-08 | 2014-08-12 | Biota Scientific Management Pty Ltd. | Bicyclic nucleosides and nucleotides as therapeutic agents |
GB0505781D0 (en) | 2005-03-21 | 2005-04-27 | Univ Cardiff | Chemical compounds |
ATE517897T1 (en) | 2005-03-25 | 2011-08-15 | Tibotec Pharm Ltd | HETEROBICYCLIC INHIBITORS OF HVC |
WO2006116557A1 (en) | 2005-04-25 | 2006-11-02 | Genelabs Technologies, Inc. | Nucleoside compounds for treating viral infections |
WO2006119347A1 (en) | 2005-05-02 | 2006-11-09 | Pharmaessentia Corp. | STEREOSELECTIVE SYNTHESIS OF β-NUCLEOSIDES |
WO2006121820A1 (en) | 2005-05-05 | 2006-11-16 | Valeant Research & Development | Phosphoramidate prodrugs for treatment of viral infection |
AR056347A1 (en) | 2005-05-12 | 2007-10-03 | Tibotec Pharm Ltd | USE OF PTERIDINE COMPOUNDS TO MANUFACTURE PHARMACEUTICAL MEDICINES AND COMPOSITIONS |
WO2007027248A2 (en) * | 2005-05-16 | 2007-03-08 | Valeant Research & Development | 3', 5' - cyclic nucleoside analogues for treatment of hcv |
US8143288B2 (en) | 2005-06-06 | 2012-03-27 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
TWI471145B (en) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | Unitary pharmaceutical dosage form |
TWI375560B (en) * | 2005-06-13 | 2012-11-01 | Gilead Sciences Inc | Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same |
US10532028B2 (en) * | 2005-07-28 | 2020-01-14 | Isp Investments Llc | Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced |
US20070059360A1 (en) * | 2005-07-29 | 2007-03-15 | Ashish Jaiswal | Water-dispersible anti-retroviral pharmaceutical compositions |
BRPI0614638A2 (en) | 2005-07-29 | 2011-04-12 | Tibotec Pharm Ltd | macrocyclic hepatitis c virus inhibitor compounds, use thereof, process for their preparation, combination and pharmaceutical composition |
PE20070211A1 (en) | 2005-07-29 | 2007-05-12 | Medivir Ab | MACROCYCLIC COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS |
SI1912997T1 (en) | 2005-07-29 | 2012-02-29 | Tibotec Pharm Ltd | Macrocyclic inhibitors of hepatitis c virus |
EA014293B1 (en) | 2005-07-29 | 2010-10-29 | Тиботек Фармасьютикалз Лтд. | Macrocyclic inhibitors of hepatitus c virus |
CN101273042B (en) | 2005-07-29 | 2013-11-06 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis C virus |
CA2618335C (en) * | 2005-08-15 | 2015-03-31 | F.Hoffmann-La Roche Ag | Antiviral phosphoramidates of 4'-substituted pronucleotides |
GB0519488D0 (en) | 2005-09-23 | 2005-11-02 | Glaxo Group Ltd | Compounds |
GB0519478D0 (en) | 2005-09-23 | 2005-11-02 | Glaxo Group Ltd | Compounds |
CN101336247B (en) | 2005-12-09 | 2013-01-23 | 豪夫迈·罗氏有限公司 | Antiviral nucleosides |
NZ544187A (en) | 2005-12-15 | 2008-07-31 | Ind Res Ltd | Deazapurine analogs of 1'-aza-l-nucleosides |
GB0602046D0 (en) | 2006-02-01 | 2006-03-15 | Smithkline Beecham Corp | Compounds |
WO2007092000A1 (en) | 2006-02-06 | 2007-08-16 | Bristol-Myers Squibb Company | Inhibitors of hcv replication |
US7879815B2 (en) | 2006-02-14 | 2011-02-01 | Merck Sharp & Dohme Corp. | Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection |
ES2374455T3 (en) | 2006-02-17 | 2012-02-16 | Pfizer Limited | DERIVATIVES OF 3-DEAZAPURINZA AS MODULATORS OF TLR7. |
US8895531B2 (en) | 2006-03-23 | 2014-11-25 | Rfs Pharma Llc | 2′-fluoronucleoside phosphonates as antiviral agents |
JP5205370B2 (en) | 2006-05-25 | 2013-06-05 | ブリストル−マイヤーズ スクイブ カンパニー | Cyclopropyl condensed indolobenzazepine HCVNS5B inhibitor |
EP2043613A1 (en) * | 2006-07-14 | 2009-04-08 | Fmc Corporation | Solid form |
EP1881001A1 (en) | 2006-07-20 | 2008-01-23 | Tibotec Pharmaceuticals Ltd. | HCV NS-3 serine protease inhibitors |
MX2009003795A (en) | 2006-10-10 | 2009-06-18 | Pharmasset Inc | Preparation of nucleosides ribofuranosyl pyrimidines. |
PL216525B1 (en) | 2006-10-17 | 2014-04-30 | Ct Badań Molekularnych I Makromolekularnych Polskiej Akademii Nauk | 5'-0-[(N-acyl) amidophosphate] - and 5'-0- [(N-acyl) amidothiophosphate]- and 5'-0- [N-acyl) amidodithiophosphate] and 5'-0- [N-acyl) amidoselenophosphate] - nucleosides and method for their manufacture |
GB0623493D0 (en) | 2006-11-24 | 2007-01-03 | Univ Cardiff | Chemical compounds |
US8148349B2 (en) | 2006-12-20 | 2012-04-03 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Nucleoside cyclic phosphoramidates for the treatment of RNA-dependent RNA viral infection |
US7951789B2 (en) | 2006-12-28 | 2011-05-31 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8071568B2 (en) * | 2007-01-05 | 2011-12-06 | Merck Sharp & Dohme Corp. | Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection |
CN101765369A (en) | 2007-03-19 | 2010-06-30 | 俄勒冈州由俄勒冈州立大学代表州高等教育委员会行使 | Mannich base N-oxide drugs |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
GB0709791D0 (en) | 2007-05-22 | 2007-06-27 | Angeletti P Ist Richerche Bio | Antiviral agents |
CN100532388C (en) | 2007-07-16 | 2009-08-26 | 郑州大学 | 2'-fluorine-4'-substituted-nucleosides analog, preparation method and uses thereof |
CN101108870A (en) | 2007-08-03 | 2008-01-23 | 冷一欣 | Process for preparation of nucleoside phosphoric acid ester compound and application thereof |
AU2008292910A1 (en) | 2007-08-31 | 2009-03-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compounds for inhibiting Wip1, prodrugs and compositions thereof, and related methods |
JO2778B1 (en) | 2007-10-16 | 2014-03-15 | ايساي انك | Certain Compounds, Compositions and Methods |
JP5238939B2 (en) | 2007-11-07 | 2013-07-17 | 三菱化学株式会社 | Long fiber reinforced composite resin composition and molded product |
US20090318380A1 (en) | 2007-11-20 | 2009-12-24 | Pharmasset, Inc. | 2',4'-substituted nucleosides as antiviral agents |
WO2009086192A1 (en) | 2007-12-21 | 2009-07-09 | Alios Biopharma, Inc. | Biodegradable phosphate protected nucleotide derivatives and their use as cancer, anti viral and anti parasitic agents |
US8227431B2 (en) | 2008-03-17 | 2012-07-24 | Hetero Drugs Limited | Nucleoside derivatives |
WO2009120878A2 (en) | 2008-03-26 | 2009-10-01 | Alnylam Pharmaceuticals, Inc. | Non-natural ribonucleotides, and methods of use thereof |
WO2009129120A2 (en) | 2008-04-15 | 2009-10-22 | Rfs Pharma, Llc | Nucleoside derivatives for treatment of caliciviridae infections, including norovirus infections |
HUE025528T2 (en) | 2008-04-23 | 2016-05-30 | Gilead Sciences Inc | 1' -substituted carba-nucleoside analogs for antiviral treatment |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8173621B2 (en) * | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
EP2346329B1 (en) | 2008-10-09 | 2013-08-21 | Anadys Pharmaceuticals, Inc. | A method of inhibiting hepatitis c virus by combination of a 5,6-dihydro-1h-pyridin-2-one and one or more additional antiviral compounds |
MX2011006890A (en) | 2008-12-23 | 2011-07-20 | Pharmasset Inc | Nucleoside analogs. |
TW201026715A (en) | 2008-12-23 | 2010-07-16 | Pharmasset Inc | Nucleoside phosphoramidates |
JP5793084B2 (en) | 2008-12-23 | 2015-10-14 | ギリアド ファーマセット エルエルシー | Synthesis of purine nucleosides |
AU2010203660A1 (en) | 2009-01-07 | 2011-07-28 | Scynexis, Inc | Combination of a cyclosporine derivative and nucleosides for treating HCV |
JO3027B1 (en) | 2009-05-14 | 2016-09-05 | Janssen Products Lp | Uracyl Spirooxetane Nucleosides |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI576352B (en) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | Nucleoside phosphoramidates |
US8719767B2 (en) | 2011-03-31 | 2014-05-06 | Commvault Systems, Inc. | Utilizing snapshots to provide builds to developer computing devices |
NZ599402A (en) | 2009-09-21 | 2014-02-28 | Gilead Sciences Inc | 2’ -fluoro substituted carba-nucleoside analogs for antiviral treatment |
US7973013B2 (en) | 2009-09-21 | 2011-07-05 | Gilead Sciences, Inc. | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment |
PT2552930E (en) | 2010-03-31 | 2015-11-17 | Gilead Pharmasset Llc | Crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1-(2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
PL3290428T3 (en) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
CA2818853A1 (en) | 2010-11-30 | 2012-06-07 | Gilead Pharmasset Llc | 2'-spirocyclo-nucleosides for use in therapy of hcv or dengue virus |
-
2009
- 2009-06-05 US US12/479,075 patent/US8173621B2/en active Active
- 2009-06-08 WO PCT/US2009/046619 patent/WO2009152095A2/en active Application Filing
- 2009-06-08 ES ES09763386.1T patent/ES2536727T3/en active Active
- 2009-06-08 CN CN200980131006XA patent/CN102119167A/en active Pending
- 2009-06-08 CA CA2727495A patent/CA2727495C/en not_active Expired - Fee Related
- 2009-06-08 AU AU2009257647A patent/AU2009257647C1/en not_active Ceased
- 2009-06-08 EP EP09763386.1A patent/EP2313422B1/en active Active
- 2009-06-08 MX MX2010013768A patent/MX2010013768A/en active IP Right Grant
- 2009-06-08 JP JP2011513609A patent/JP5749160B2/en not_active Expired - Fee Related
- 2009-06-08 KR KR1020117000655A patent/KR101682494B1/en active Application Filing
- 2009-06-08 KR KR1020167033252A patent/KR20160139060A/en not_active Application Discontinuation
- 2009-06-08 BR BRPI0915484A patent/BRPI0915484A2/en not_active IP Right Cessation
- 2009-06-08 PT PT97633861T patent/PT2313422E/en unknown
- 2009-06-10 TW TW098119376A patent/TW201002733A/en unknown
- 2009-06-11 AR ARP090102112A patent/AR072104A1/en not_active Application Discontinuation
- 2009-06-11 UY UY0001031892A patent/UY31892A/en not_active Application Discontinuation
-
2010
- 2010-12-08 ZA ZA2010/08829A patent/ZA201008829B/en unknown
- 2010-12-09 IL IL209916A patent/IL209916A/en not_active IP Right Cessation
- 2010-12-10 CL CL2010001407A patent/CL2010001407A1/en unknown
- 2010-12-29 CO CO10164099A patent/CO6321272A2/en active IP Right Grant
-
2012
- 2012-04-05 US US13/439,991 patent/US8759510B2/en active Active
-
2015
- 2015-05-12 JP JP2015097298A patent/JP2015180655A/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2009152095A3 * |
Also Published As
Publication number | Publication date |
---|---|
JP2011524356A (en) | 2011-09-01 |
CA2727495C (en) | 2017-08-29 |
IL209916A0 (en) | 2011-02-28 |
AU2009257647A1 (en) | 2009-12-17 |
MX2010013768A (en) | 2011-03-03 |
ZA201008829B (en) | 2011-09-28 |
JP5749160B2 (en) | 2015-07-15 |
WO2009152095A2 (en) | 2009-12-17 |
AU2009257647B2 (en) | 2014-04-10 |
ES2536727T3 (en) | 2015-05-28 |
EP2313422B1 (en) | 2015-03-04 |
AR072104A1 (en) | 2010-08-04 |
KR20160139060A (en) | 2016-12-06 |
AU2009257647C1 (en) | 2014-10-23 |
UY31892A (en) | 2010-01-05 |
CN102119167A (en) | 2011-07-06 |
JP2015180655A (en) | 2015-10-15 |
BRPI0915484A2 (en) | 2019-09-17 |
CO6321272A2 (en) | 2011-09-20 |
US8759510B2 (en) | 2014-06-24 |
US8173621B2 (en) | 2012-05-08 |
KR20110016501A (en) | 2011-02-17 |
PT2313422E (en) | 2015-06-05 |
CA2727495A1 (en) | 2009-12-17 |
WO2009152095A3 (en) | 2010-11-04 |
US20100081628A1 (en) | 2010-04-01 |
IL209916A (en) | 2014-04-30 |
US20120258928A1 (en) | 2012-10-11 |
TW201002733A (en) | 2010-01-16 |
CL2010001407A1 (en) | 2011-05-06 |
KR101682494B1 (en) | 2016-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2313422B1 (en) | Nucleoside cyclicphosphates | |
AU2009329867B2 (en) | Nucleoside phosphoramidates | |
AU2009329917B2 (en) | Nucleoside analogs | |
JP2011524356A5 (en) | ||
EP2824109A1 (en) | Nucleoside phosphoramidate prodrugs | |
AU2014233579B2 (en) | Nucleoside phosphoramidate prodrugs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20101230 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA RS |
|
DAX | Request for extension of the european patent (deleted) | ||
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: GILEAD PHARMASSET LLC |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: GILEAD PHARMASSET LLC |
|
17Q | First examination report despatched |
Effective date: 20130507 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20140912 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: MARKS AND CLERK (LUXEMBOURG) LLP, CH |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 713788 Country of ref document: AT Kind code of ref document: T Effective date: 20150415 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602009029805 Country of ref document: DE Effective date: 20150416 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2536727 Country of ref document: ES Kind code of ref document: T3 Effective date: 20150528 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20150512 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: T3 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150604 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150605 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150704 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602009029805 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
26N | No opposition filed |
Effective date: 20151207 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150608 Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: UEP Ref document number: 713788 Country of ref document: AT Kind code of ref document: T Effective date: 20150304 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20090608 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 9 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 10 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20150304 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PT Payment date: 20180521 Year of fee payment: 10 Ref country code: NL Payment date: 20180626 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20180627 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20180704 Year of fee payment: 10 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20191209 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MM Effective date: 20190701 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 713788 Country of ref document: AT Kind code of ref document: T Effective date: 20190608 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20190630 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190608 Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190701 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190630 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190630 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190630 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20230510 Year of fee payment: 15 Ref country code: IE Payment date: 20230412 Year of fee payment: 15 Ref country code: DE Payment date: 20230412 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20230420 Year of fee payment: 15 Ref country code: ES Payment date: 20230707 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20240328 Year of fee payment: 16 |